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CA3049643A1 - Novel heterocyclic compound, its preparation method, and pharmaceutical composition comprising the same - Google Patents

Novel heterocyclic compound, its preparation method, and pharmaceutical composition comprising the same Download PDF

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Publication number
CA3049643A1
CA3049643A1 CA3049643A CA3049643A CA3049643A1 CA 3049643 A1 CA3049643 A1 CA 3049643A1 CA 3049643 A CA3049643 A CA 3049643A CA 3049643 A CA3049643 A CA 3049643A CA 3049643 A1 CA3049643 A1 CA 3049643A1
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Prior art keywords
piperidin
benzo
propyl
imidazol
chloro
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CA3049643C (en
Inventor
Bong-Yong Lee
Min-Jae Cho
Hyung-Geun Lee
Myung-gi JUNG
Yunju OH
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Daewoong Pharmaceutical Co Ltd
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Daewoong Pharmaceutical Co Ltd
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract

The present invention relates to a heterocyclic compound represented by Chemical Formula 1 that can be used for the prevention or treatment of diseases caused by abnormality in a PRS (prolyl-tRNA synthetase) activity, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition comprising the same.

Description

TITLE OF INVENTION
NOVEL HETEROCYCLIC COMPOUND, ITS PREPARATION METHOD, AND
PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
TECHNICAL FIELD
The present invention relates to a heterocyclic compound having a novel structure that can be used for the prevention or treatment of diseases caused by abnormality in a PRS (prolyl-tRNA synthetase) activity, a method for preparing the same, and a pharmaceutical composition comprising the same.
BACKGROUND OF ART
PRS (prolyl-tRNA synthetase) is one of the aminoacyl-tRNA synthetase (ARS) family and serves to activate an amino acid for protein synthesis. That is, ARS NI __ forms a translational function to form aminoacyl adenylate (AA-AMP) and then transfer the activated amino acid to the 3-end of the corresponding tRNA. Since ARS plays an important role in the synthesis of protein, ARS inhibitors suppress the growth of all cells. Thus, ARS has been recognized as a promising target for a therapeutic agent for treating diseases that should suppress antibiotics or cell overexpression (Nature, 2013, 494:121-125).
PRS is present in, or functions as, a multi-synthetase complex (MSC) in the form of EPRS (Glutainyl-Prolyl-tRNA Synthetase). In particular, among various MSCs, EPRS functions as a translational silencer that suppresses the production of VEGF A (vascular endothelial growth factor A) which is a key factor in angiogenesis. In addition, it is reported that EPRS is closely related with various solid tumors (Nat. Rev. Cancer, 2011, 11, 708-718).
The only substance, known as the PRS inhibitor, is halofuginone. Halofuginone is a derivative of febrifugine derived from natural products and has anti-malarial effects and various anti-inflammatory effects. It can also be used as an animal feed additive. In addition, it has been reported that halofuginone increases the phosphorylation of GCN2 kinase through PRS inhibition, which induces ATF4 and CHOP expression, and thus promotes cell death (Nat.
Chem. Biol. 2012, 8, 311-317). Currently, halofuginone is being clinically studied as anti-cancer agent, an anti-inflammatory agent (J immunol, 2014, 192(5), 2167-76), therapeutic agents for the treatment of autoimmune diseases (Arthritis Rheumatol, 2014,66 (5), 1195-207), therapeutic agents for the treatment of fibrosis diseases (World J Gastroenterol, 2014,20 (40), 14778-14786), and the like (Bioorg. Med. Chem. 2014, 22, 1993-2004).
However, it has been reported that halofuginone acts on various targets and has a very severe toxicity and further there is a risk of genotoxicity (The EFSA Journal, 2003. 8: 1-45).
Therefore, discovering PRS inhibitors having higher safety to the human body among substances capable of inhibiting PRS like halofuginone has a significance in terms of developing an anti-cancer agent of the next generation that can be used as an antifibrosis agent, an anti-inflammatory agent, an autoimmune therapeutic agent alone or in combination with an existing targeted anti-cancer agent.
In this regard, the present inventors have conducted numerous studies to develop a novel compound with reduced toxicity while having a PRS enzyme inhibitory effect, and found that the compound having a novel structure which will be described later selectively inhibits the PRS, thereby completing the present invention. The compounds belonging to the present invention themselves have mainly a PRS enzyme inhibitory activity, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.
DETAILED DESCRIPTION OF THE INVENTION
TECHNICAL PROBLEM
It is an object of the present invention to provide a heterocyclic compound having a novel structure that can be used for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases or fibrosis, a method for preparing the same, and a pharmaceutical composition comprising the same.
TECHNICAL SOLUTION
In order to achieve the above object, the present invention provides a compound represented by the following Chemical Formula I, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

, OH
Xi--X2 N,-- _____________ L N
A
in Chemical Formula 1, n is 1, or 2, L is -CH)CH2-, -CH=C(R')-, or wherein R' is hydrogen, C 1_4 alkyl, or halogen, X1 is CR] R2, NRI, or X2 is CR3R4, or NR3, wherein R1 to R4 are each independently hydrogen, C14 alkyl, C1.4 hydroxyalkyl, hydroxy, amino, carboxy, -COO(C14 alkyl), -CON1-12, -CONH(C14 alkyl), -CON
(C1_4 alky1)2, or pyrazolyl unsubstituted or substituted with C14 haloalkyl; or R1 and R3, together with each other, link X1 and X2 via a double bond, and A is benzene, pyridine, pyrimidine, or pyrimidinedione ring, wherein A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of a ring-type substituent selected from the group consisting of fur-anyl, imidazolyl, isoxazolyl, phenyl, pyrazolyl, pyridinonyl, pyridinyl, thiazoly1, and thiophenyl; Ci4 alkyl; C14 alkoxy; Ci4 haloalkyl; CIA
haloalkoxy; halogen;
di(C14 alkyl)amino; nitro; -COO(C1.4 alkyl); dihydropyranyl; morpholino;
piperidinyl; and pyrrolidinyl; and wherein the ring-type substituent is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C1_5 alkyl, C14 haloalkyl, C3.6 cycloalkyl, monovalent of C2_5 alkylene carbonate, -COO(C14 alkyl), halogen, cyano, thiazolyl, and (1,3-dioxolan-2-yl)methyl.
Preferably, when the ring-type substituent is furanyl, it is unsubsituted or substituted with
2 -COO(C IA alkyl). When the ring-type substituent is imidazolyl, it is unsubsituted or substituted with C1.5 alkyl. When the ring-type substituent is isoxazolyl, it is unsubsituted or substituted with two C1.5 alkyls. When the ring-type substituent is phenyl, it is unsubsituted or substituted with halogen, or C14 haloalkyl. When the ring-type substituent is pyrazolyl, it is unsubsituted or
3 substituted with C1_5 alkyl, Ci4 haloalkyl, monovalent of C2_5 alkylene carbonate, thiazolyl, and (1,3-dioxolan-2-ypinethyl. When the ring-type substituent is pyridinonyl, it is unsubsituted or substituted with C1_5 alkyl. When the ring-type substituent is pyridinyl, it is unsubsituted or substituted with halogen. When the ring-type substituent is pyrrolyl, it is unsubsituted or substituted with C1.5 alkyl and -COO(C14 alkyl). When the ring-type substituent is thiazolyl, it is unsubsituted or substituted with C1_5 alkyl, C3.{, cycloalkyl, cyano, or monovalent of C2-5 alkylene carbonate. When the ring-type substituent is thiophenyl, it is unsubsituted or substituted with one or two substituents each independently selected from the group consisting of C1_5 alkyl, and -COO(C14 alkyl).
Preferably, A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of C14 alkyl; C14 alkoxy; C14 haloalkyl;
halogen; phenyl unsubstituted or substituted with halogen, or C14 haloalkyl;
pyrazolyl unsubstitued or substituted with Ci_5 alkyl, thiazolyl, or Ci_4 haloalkyl;
thiopheny unsubstituted or substituted with C1_5 alkyl, or -COO(C14 alkyl); pyrrolyl unsubstituted or substituted with C1-5 alkyl and/or -COO(C14 alkyl); di(C14 alkyl)amino; morpholino; piperidinyl;
furanyl: and pyrrolidinyl.
Preferably, L is -CH2CH2-, -CH=CH-, -CH=CF-, -CH=C(CH3)-, or Preferably, according to X1 and X2, the compound represented by Chemical Formula I is represented by the following Chemical Formulas 1-1 to 1-5:
(7[Chemical Formula 1-1]
.-t¨T7 _________________ I OH R2 N,-- _____________ L N
A
[Chemical Formula 1-2]
4 L N
A
[Chemical Formula 1-3]

ty0H N/
_________________ L N
[Chemical Formula 1-4]

OH

<fris"/ R 1 N _______________ L N
[Chemical Formula 1-5]

OH
N _______________ LN
in Chemical Formulas 1-1 to 1-5, n, L, R1 to R4 and A are as previously defined.
Preferably, R1 to R4 are each independently hydrogen, methyl, hydroxymethyl, hydroxy, amino, carboxy, -COOCH3, -CONH2, -CONFICH3, or -CON(CH3)2; or R1 and R3, together with each other, link X1 and X2 via a double bond.
Preferably, A is benzene, pyridine, pyrimidine, or pyrimidinedione ring, wherein A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of methyl, isobutyl, methoxy, trifluorornethyl, fluoro, chloro, bromo, phenyl, phenyl substituted with fluoro, phenyl substituted with chloro, phenyl substituted with trifluoromethyl, thiophenyl, thiopheny substituted with methyl, thiopheny substituted with -
5
6 PCT/KR2018/001625 COOCH3, pyrazolyl substituted with difluoromethyl, pyrazolyl substituted with methyl, pyrazolyl substituted with thiazolyl, pyrrolyl substituted with methyl and -COOCH2CE-I3, furanyl, climethylamino, diethylamino, methytethylamino, tnorpholino, piperidinyl, and pyrrolidinyl.
Preferably, A is benzene, wherein A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of C14 alkyl; C14 alkoxy;
halogen; and phenyl unsubstituted or substituted with halogen or Ci4haloalkyl.
Preferably, A is pyridine, wherein A is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C1.4 alkyl; C1.4 haloalkyl;
halogen; and phenyl substituted with halogen.
Preferably, A is pyrimidine, wherein A is substituted with a substituent selected from the group consisting of halogen; di(C14 alkyl)amino; morpholino; piperidinyl; and pyrrolidinyl.
Preferably, A is pyrimidinedione, wherein A is unsubstituted or substituted with one or two C
Typical examples of the compounds represented by Chemical Formula I are as follows:
I) (2R,3S)-2-(3-(6-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 2) (2R,3S)-2-(3-(4-bromo- I H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 3) (2R,3S)-2-(3-(5-bromo-11-1-benzo[d]imidazol-1-y0propyl)piperidin-3-ol, 4) (2R,3S)-2-(3-(6-bromo-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 5) (2R,3S)-2-(3-(7-bromo-1H-benzo[d]im idazol-1-y1)propyl)piperidin-3-ol, 6) (2R,3S)-2-(3-(4-fluoro-1H-benzo[d]imidazol-1-y0propyl)piperidin-3-ol,
7) (2R,3S)-2-(3-(5-fluoro-1H-benzo[d]imidazol- I -yl)propyl)piperidin-3-ol,
8) (2R,3S)-2-(3-(6-fluoro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
9) (2R3S)-2-(3-(7-fluoro-114-benzo[d]imidazol-1-Y1)propyl)piperidin-3-ol,
10) (2R,3S)-2-(3-(4-chloro-IH-benzo[d]imidazol-1-yl)propyl)pipendin-3-ol,
11) (2R,3S)-2-(3-(5-chloro-1H-benzo[d]imidazol-1-y0propyl )piperidin-3-ol,
12) (2R,3S)-2-(3-(7-chloro-1H-benzo[d]imidazol-1-3/1)propy1)piperidin-3-ol,
13) (2R,3S)-2-(3-(6-methy1-1H-benzo[d]imidazo1-1-yl)propyl)piperidin-3-ol,
14) (2R,3S)-2-(3-(5-methyl-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
15) (2R,3 S)-2-(3-(6-(trifluoromethyl)-1H-benzo[d] imidazol-1-yl)propyl)piperidin-3-ol,
16) (2R ,3S)-2-(3-(7-(trifluoromethyl)-114-benzo[d] imidazol-1-yl)propyl)piperidin-3-ol,
17) (2R,3S)-2-(3-(7-(trifluoromethoxy)-1H-benzo[d]imidazo1-1-yl)propyl)piperidin-3-ol,
18) (2R,3S)-2-(3-(4-(pyrrolidin-l-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol,
19) (2R,3S)-2-(3-(4-(piperidin-1-y1)-11-1-benzo[d]imidazol-1-yl)propyppipendin-3-ol,
20) (2R,3 S)-2-(3-(4-(3-fluorOpheny1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-1 5 ol,
21) (2R,3S)-2-(3-(4-(3-ehloropheny1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol,
22) (2R,3S)-2-(3-(5-(3-fluoropheny1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
23) (2R,3S)-2-(3-(6-(2-fluoropheny1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-ol,
24) (2R,3S)-2-(3-(6-(3-fluoropheny1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
25) (2R,3 S)-2-(3-(6-(4-fluoropheny1)-1H-benzo[d] imidazol-1-yl)propyl)piperidi n-3-2 5 ol,
26) (2 R,3S)-2-(3-(7-(2-fluoropheny1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
27) (2R,3S)-2-(3-(7-(3-fluoropheny1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
28) (2R,3 S)-2-(3-(7-(4-fluoropheny1)-1H-benzo[d]im idazol-I-Apropyl)pipendin-3 -ol,
29) (2R,3S)-2-(3-(5-(1H-pyrazol-4-y1)-1H-benzo[dlimidazol-1-yl)propyppiperidin-3-ol,
30) (2R,3S)-2-(3-(6-( 1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
31) (2R,3S)-2-(3-(7-(1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol,
32) (2R,3S)-2-(3-(6-c1i1oro-5-fluoro-1H-benzo[d]im idazol-1-yl)propyl)piperidin-3-ol,
33) (2R,3S)-2-(3-(6-bromo-5-fluoro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
34) (2R,3S)-2-(3-(5-chloro-6-fluoro- 1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol,
35) (2R,3S)-2-(3-(5-bromo-6-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-1 5 ol,
36) (2R,3S)-2-(3-(6-bromo-5-chloro- IH-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, = 37) (2R,3S)-2-(3-(6-chloro-5-methoxy-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 38) (2R,3S)-2-(3-(6-fluoro-5-methoxy-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 39) (2R,3S)-2-(3-(5-fluoro-6-methy1-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 40) (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yppropyl)piperidin-3-ol, 41) (2S,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 42) (2S,3R)-2-(3-(4,5-dichloro-1H-benzo[d]irnidazol-1-y1)propyl)piperidin-3-ol, 43) (2R,3R)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 44) (2R,3S)-2-(3-(4-chloro-5-methyl-1H-benzo[d]imidazol-1-y1 )propyl)pipendin-3-ol, 45) (2R,3S)-2-(3-(5-bromo-4-methy1-1H-benzo[d] im idazol-1-yl)propyl)piperidin-3-ol, 46) (2R,3S)-2-(3-(5-chloro-4-methy1-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 47) (2R,3S)-2-(3-(5-bromo-4-fluoro-1H-benzo[dJim idazol-1-yl)propyl)piperidin-3-01, 48) (2R,3S)-2-(3-(6-bromo-7-fluoro-1H-benzo[d]imidazol-1-yppropyl)piperidin-ol, 49) (2R,3S)-2-(3-(4,5-difluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 50) (2R,3S)-2-(3-(6,7-difluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 51) (2R,3S)-2-(3-(4,5-dirnethy1-1H-benzo[d]irnidazol-1-yl)propyl)piperidin-3-ol, 52) (2R,3S)-2-(3-(5,6-difluoro-1H-benzo[d]imidazol-1-yppropyl)piperidin-3-ol, 53) (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[dlimidazol-1-yl)propyl)piperidin-3-ol, 54) (2R,3S)-2-(3-(5,6-dibromo-11-1-benzo[d]Unidazol-1-yl)propyl)piperidin-3-ol, 55) (2R,3S)-2-(3-(5,6-dimethy1-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 56) (2R,3S)-2-(3-(6,7-dichloro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-01, 57) (2R,3S)-2-(3-(4,6-difluoro-1H-benzo[d]imidazol-1-yppropy0piperidin-3-ol, 58) (2R,3S)-2-(3-(5,7-difluoro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 59) (2R,3S)-2-(3-(4-chloro-5-rnethoxy-IH-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 60) (2R,3S)-2-(3-(7-chloro-6-methoxy-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 61) (2R,3S)-2-(3-(6-chloro-4-methy1-1H-benzo[d]imidazol-1-yl)propyppiperidin-3-ol, 62) (2R,3S)-2-(3-(4-chloro-5-fluoro-1H-benzo[d]im idazol-1-y1)propyl)piperidin-3-2 5 ol, 63) (2R,3S)-2-(3-(6-bromo-4-methy1-1H-benzo[d]imidazol-1-y1 )propyl)piperidin-3-o1, 64) (2R,3S)-2-(3-(5-fluoro-4-methy1-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, - 30 65) (2R,3S)-2-(3-(6-fl uoro-7-methyl-1 H-benzo[d]im idazol-1-yl)propyl)piperidin-3-W() 2018/147626 PCT/KR2018/001625 ol, 66) (2R,3S)-2-(3-(4-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yppropyppiperidin-3-01, 67) (2R,3S)-2-(3-(7-chloro-6-,(trifluoromethyl)-11-f-benzo[d]imidazol-1 -yl)propyl)piperidin-3-ol, 68) methyl 7-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-benzo[d]imidazole-5-carboxylate, 69) (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 70) (2R,3S)-2-(3-(5-bromo-7-chloro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 71) (2R,3S)-2-(3-(7-bromo-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 72) (2R,3S)-2-(3-(6-bromo-4-fluoro-1H-benzo[d]imidazol-1-yppropyl)piperidin-ol, 73) (2R,3S)-2-(3-(5-bromo-7-fluoro- I FI-benzo[d]imidazol-1-y1)propyppiperidin-3-ol, 74) (2 R,3S)-2-(3-(7-chloro-4-fluoro-11-1-benzo[d]im idazol-1-y1)propyl)piperidin-3-ol, 75) (2R,3S)-2-(3-(5-bromo-4-nitro- I H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 76) (2R,3S)-2-(3-(6-bromo-7-nitro-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 77) (2R,3S)-2-(3-(4-chloro-5-nitro-1H-benzo[d]imidazol-1-yl)propyl)pipericlin-3-ol, 78) (2R,3S)-2-(3-(7-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yppropyl)piperidin-3-ol, 79) (2R,3S)-2-(3-(5-ehloro-7-fluoro-1H-benzo[cf]imidazol-1-yl)propyl)piperidin-3-ol, 80) (2R,3S)-2-(3-(5,7-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 81) (2R,3S)-2-(3-(5-chloro-7-(1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 82) (2R,3S)-2-(3-(7-( I H-pyrazol-4-y1)-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 83) (2R,3S)-24345-chloro-743-fluoropheny1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 84) (2R,3S)-243-(743-fluoropheny1)-54trifluoromethyl)-1H-benzo[d]im idazol-yl)propyl)pipericiin-3-ol, 85) (2R,3S)-24345-chloro-742-methylthiazol-5-y1)-1H-benzo[d]imidazol- 1-yl)propyl)piperidin-3-ol, 86) (2R,3S)-243-(5-chloro-7-(pyridin-3-y1)-1H-benzo[d]imidazol- 1-yl)propyl)piperidin-3-ol, 87) (2R,3S)-2-(3-(5-chloro-745-fluoropyridin-3-y1)- 1H-benzo[d]imidazol-1-yl)propyl)piperidi n-3-01, 88) 5(5-chloro-1434(2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1 Fl-benzo[d]imidazol-7-yl)-89) (2R,3S)-243-(5-chloro-741-(ditluoromethyl)-1H-pyrazol-4-y1)-1H-1 5 benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 90) (2R,3S)-243-(5-chloro-7-(isoxazol-3-y1)-11-1-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 91) (2R,3S)-243-(5-chloro-7-(thiophen-3-y1)-1H-benzo[d]imidazol- 1-yl)propyl)piperidin-3-ol, 92) (2R,3S)-243-(5-chloro-742-methylthiophen-3-y1)-1H-benzo[d]imidazol- 1-yl)propyl)piperidi n-3-ol, 93) (2R,3S)-243-(5-chloro-743,5-dimethylisoxazol-4-y1)-1H-benzo[d]imidazol-yl)propyl)piperidin-3-ol, 94) (2R,3S)-243-(5-chloro-743,6-d ihydro-2H-pyran-4-y1)-1H-benzo[djimidazol-yl)propyl)piperidin-3-ol, 95) (2R,3S)-243474 1 41 ,3-dioxolan-2-y1)rnethyl)-1H-pyrazol-4-y1)-5-chloro-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 96) (2R,3S)-2-(3-(5-chloro-7-(1-methy1-1H-imidazol-5-y1)-1H-benzo[d]im idazol-1-yl)propyl)piperidin-3-ol, 97) (2R,3S)-2-(3-(5-chloro-7-(1-methy1-1H-pyrazol-4-34)- 1H-benzo[d] i m idazo I- 1 -y1)propyl)piperidin-3-01, 98) (2R,3S)-2-(3-(7-(pyrrolidin- 1 -y1)-1H-benzordlimidazol-1-y1)propyl)piperidin-3-ol, 99) (2R,3S)-2-(3-(5-chloro-7-(pyrrolidin- I -y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 100) (2R,3S)-2-(3-(5-chloro-7-(2-cyclopropylthiazol-5-y1)-1H-benzo[d]imidazol-y1)propyl)piperidin-3-ol, 101) (2R,3S)-2-(3-(5-chloro-7-(1-(thiazol-2-y1)-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yppropyppiperidin-3-ol, 102) (2R,3S)-2-(3-(5-chloro-7-(1-(oxetan-3-y1)-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 103) (2R,3S)-2-(3-(5-chloro-7-(2-(tetrahydro-2H-pyran-4-yl)thiazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 104) 1-15(2R,3S)-2-(3-(5-chloro-7-(furan-3-y1)-1H-benzo[d]imidazol-yppropyl)piperidin-3-ol, 105) 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-111-benzo[d]imidazol-7-y1)thiazole-2-carbonitrile, 106) (2R,3S)-2-(3-(7-(1-(tert-buty1)-1H-pyrazol-4-y1)-5-ch1oro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 107) (2R,3S)-2-(3-(5-chloro-7-(1-isopenty1-1H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 108) (2R,3S)-2-(3-(5-chloro-7-(1-isopropyl- I H-pyrazol-4-y1)-1H-benzo[dJimidazol-1-y1)propyl)piperidin-3-01, 109) (2R,3S)-2-(3-(5-chloro-7-(4-methylthiophen-3-yI)- I H-benzo[d] imidazol-1-2 5 yl)propyl)piperidin-3-ol, 110) ethyl 3-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-benzo[d]imidazol-7-y1)furan-2-carboxylate, 111) methyl 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-benzo[d]imidazol-7-ypthiophene-2-carboxylate, 112) (2R,3S)-2-(3-(5-chloro-7-(1-(2-fluoroethy 1 )-1 H-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 113) (2R,3S)-2-(3-(7-(1-buty1-1H-pyrazol-4-y1)-5-chloro-IH-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 114) (2R,3S)-2-(3-(5-chloro-7-(2,5-ditnethylthiophen-3-y1)-1H-benzo[d]imidazol-yl)propyl)piperidin-3-ol, 115) (2R,3S)-2-(3-(5-chloro-7-(1-isobuty1-114-pyrazol-4-y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 116) ethyl 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-benzo[d]imidazol-7-y1)-1-methyl-IH-pyrrole-2-carboxylate, 117) (2R,3S)-2-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-l-yl)propyl)piperidin-3-ol, 118) (2R,3S)-2-(3-(5-chloro-314-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 119) (2R,3S)-2-(3-(5-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 120) (2R,3S)-2-(3-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 121) (2R,3S)-2-(3-(5-methy1-1H-imidazo[4,5-blpyridin-1-y1)propyl)piperidin-3-ol, 122) (2R,3S)-2-(3-(6-chloro- 1 H-imidazo[4,5-c]pyridin-1-yl)propyl)piperidin-3-ol.
123) (2R,3S)-2-(3-(6-chloro-3H-imidazo[4,5-c]pyridin-3-yl)propyl)piperidin-3-ol, 124) (2 R,3S)-2-(3-(6-bromo- t H-imidazo[4,5-clpyridin-l-yl)propyl)piperidin-3-ol, 125) (2R,3S)-2-(3-(6-bromo-3H-imidazo[4,5-c]pyridin-3-yl)propyl)piperidin-3-ol, 126) (2R,3S)-2-(3-(7-chloro-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 127) (2 R,3 S)-2-(3-(5,6-dichloro-1H-imidazo[4,5-Npyridin-l-yl)propyl)piperidin-3-ol, 128) (2R,3S)-2-(3-(7-bromo-1H-imidazo[4,5-c]pyridin-1-yppropyl)piperidin-3-ol, 129) (2R,3S)-2-(3-(5-(tritluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 130) (2R,3S)-2-(3-(6,7-dichloro-3H-itnidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 131) (2R,3S)-2-(3-(6-chloro-7-methy1-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 132) (2R,3 S)-2-(3-(6-bromo-7-methy1-3H-im idazo[4,5-b] pyridin-3-yl)propyl)piperidin-3-ol, 133) (2R,3S)-2-(3-(6-bromo-7-chloro-3 H-im idazo[4,5-b]pyridin-3-3 0 yl)propyl)piperidin-3-ol, 134) (2R,3S)-2-(3-(7-chloro-6-(3-ehloropheny1)-3H-imidazo[4,5-Npyridin-3-y1)propyl)piperidin-3-01, 135) (2R,3S)-2-(3-(2-ehloro-7H-purin-7-yl)propyl)piperidin-3-ol, 136) (2R,3S)-2-(3-(2-ehloro-9H-purin-9-yl)propyl)piperidin-3-ol, 137) (2R,3S)-2-(3-(6-(dimethylamino)-9H-purin-9-yl)propyl)piperidin-3-ol, 138) (2R,3S)-2-(3-(6-(diethylamino)-9H-purin-9-yl)propyl)piperidin-3-ol, 139) (2R,3S)-2-(3-(6-(ethyl(methypamino)-9H-purin-9-yl)propyl)piperidin-3-ol, 140) (2R,3S)-2-(3-(6-morpholino-9H-purin-9-yl)propyl)piperidin-3 -01, 141) (2R,3S)-2-(3-(6-(piperidin-l-y1)-9H-purin-9-yl)propyl)piperidin-3-ol, 142) (2R,3S)-2-(3-(6-(pyrrolidin- 1-y1)-9H-purin-9-yl)propyl)piperidin-3 -01, 143) 1-(3-((2R,3S)-3-hydroxypiperidin-2-yppropy1)-1H-benzo[d]imidazol-2-ol, 144) 5,6-dichloro-t-(342R,3S)-3-hydroxypiperidin-2-yppropyl)-11-1-benzo[d]imidazol-2-ol, 145) (2R,3S)-2-(3-(2-(hydroxymethyl)-1 H-benzo[d]imidazol-1-yl)propyl)piperidin-3-1 5 01, 146) (2R,3S)-2-(3-(2-(hydroxymethyl)-4,5-dimethy1-IH-benzo[d]imidazol- 1-yl)propyl)piperidin-3-ol, 147) (2R,3S)-2-(3-(5,6-dich1oro-2-(hydroxymethyl)-11-1-benzo[d]imidazol-1-y1)propyl)piperidin-3-ol, 148) (2R,3S)-2-(3-(2-amino-5,6-dichloro-IF-1-benzo[d]imidazol-1-yppropyl)piperidin-3-ol, 149) methyl 7-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-carboxylate, 150) methyl 5-bromo- -(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-2 5 carboxylate, 151) methyl 6-bromo- I -(34(2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-carboxyl ate, 152) methyl 4-chloro-1-(3-((2R3S)-3-hydroxypiperidin-2-y1)propy1)-1H-indole-3-carboxylate, 153) methyl 6-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-y1 )propy1)-1H-indole-3-carboxylate, 154) methyl 7-chloro-1-(3 -((2 R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-carboxylate, 155) (2R,3S)-2-(3-(5-chloro-3-cyclopropy1-1H-indazol-1-y1)propyl)piperidin-3-ol, 156) (2 R,3S)-2-(3-(5-chloro-3-(trifluoromethyl)-1H-indazol-1-y1)propyl)piperidin-3-ol, 157) (2R,3S)-2-(3-(5-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-y1)-1H-indazol-yppropyppiperidin-3-ol, 158) (2R,3S)-2-(3-(6-chloro-3-(1-(difluorom ethyl)-1H-pyrazol-4-y1)-1H-indazol-1 0 y1)propyl)piperidin-3-o1, 159) 1-(3-42R,3S)-3-hydroxypiperidin-2-yppropy1)-3-methyl-IH-benzo[d]imidazol-2(3H)-one, 160) 5-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)- I H-benzo[d]
imidazol-2(3H)-one, 161) 6-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)- I H-benzo[d]
imidazol-2(3 H)-one, 162) 7-(342R,3S)-3-hydroxypiperidin-2-yl)propy1)-1,3-dimethyl-IH-purine-2,6(3H,7H)-dione, 163) 7-(3-((2R,3S )-3-hydroxypiperidin-2-yl)propy1)-3-methyl-IH-purine-2,6(3H,71-1)-2 0 dione, 164) 9-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1-methyl-IH-purine-2,6(3H,9H)-dione, 165) 7-(3-((2 R,3 S )-3-hydroxypiperidin-2-yl)propy1)-3 -isobutyl-l-methyl-1H-purine-2,6(314,7H)-dione, 166) (2R,3S)-2-((E)-3-(5,6-dichloro-IH-benzo[d]imidazol- I -yl)prop- I -enyl)piperidin-3-ol, 167) (2R,3S)-24(E)-3-(5-fluoro-4-methy1-1H-benzo[d]imidazol-1-y1)prop-1-enyl)piperidin-3-ol, 168) (2R,3S)-2-((E)-3-(5-bromo-4-methy1-1H-benzo[d]imidazol-1-y1 )prop-1-3 0 enyl)piperidin-3-ol, 169) (2R,3 S)-24(E)-3 -(5,6-dimethy1-1H-benzo[d]imidazol-1-y1)prop-1-enyl)piperidin-3-ol, 170) (2R,3S)-2-((E)-3-(5,6-dibromo-1H-benzo[d]imidazol-1-yl)prop-I-enyl)piperidin-3-ol, 171) (2R,3S)-24(E)-3-(5,6-di fluoro-1H-benzo[d] im idazol-1-Aprop-1-enyl)piperidin-3-01, 172) (2R,3S)-2-((E)-3-(4,5-dimethy1-11-1-benzo[d]imidazol-1-yl)prop-1-enyppiperidin-3-ol, 173) (2R,3S)-24(E)-3-(5-chloro-4--methyl-IH-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 174) (2R,3S)-2-((E)-3-(4,5-diehloro-1H-benzo[d]imidazol-1-yl)prop-1-en-l-yl)piperidin-3-01, 175) (2R,3S)-24(E)-3-(4-chloro-5-methy1-1H-benzo[d]imidazol-1-yl)prop-1-en-l-yl)piperidin-3-ol, 176) (2R,3S)-2-((E)-3-(5-bromo-4-nitro-1H-benzo[dlimidazol- I -yl)prop-1-en-l-yl)piperidin-3-ol, 177) (2 R,3S)-24(E)-3-(6-bromo-7-nitro-IH-benzo[dlimidazol-1-y1 178) (2R,3S)-2-((E)-3-(4-chloro-5-nitro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-.
2 0 yl)piperidin-3-ol, 179) (2R,3S)-2-((E)-3-(4,6-difluoro-1H-benzo[d] imidazol-1-yl)prop-1-en-l-yl)piperidin-3-ol, 180) (2R,3S)-2-((E)-3-(6-chloro-4-methy1-1H-benzo[d]imidazol-1-y1)prop-I-en-1-y1)piperidin-3-ol, 2 5 181) (2R,3S)-24(E)-3-(7-chloro-5-(trifluoromethyl)-1H-benzo[d]imiciazol-1-y1)prop-1-en-l-y1)piperidin-3-ol, 182) (2R,3S)-2-((E)-3-(5,7-dichloro-11-1-benzo[d]imidazol-1-y1)prop- I -en-1-yl)piperidin-3-ol, 183) (2R,3S)-2-4(E)-3-(5-chloro-7-fluoro- I H-benzo[d]imidazol-1-yl)prop-I-en-30 yl)piperidin-3-ol, 184) (2R,3S)-24(E)-3-(5-bromo-IH-imidazo[4,5-b]pyridin-l-yl)prop-1-eny1)piperidin-3-ol, 185) (2R,3S)-2-((E)-3-(7-chloro-6-(3-chloropheny1)-3H-imidazo[4,5-b]pyridin-3-yl)prop-I-enyl)piperidin-3-ol, 186) (2R,3S)-24(E)-3-(6-bromo-7-methy1-3H-imidazo[4,5-b}pyridin-3-yl)prop-1-enyl)piperidin-3-01, 187) (2R,3S)-24(E)-3-(6-bromo-7-chloro-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 188) (2R,3 S)-2-(( E)-3-(6-chloro-7-methy1-3H-imidazo[4,5-b]pyridin-3-yl)prop-enyl)piperidin-3-ol, 189) (2R,3S)-24(E)-3-(6,7-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyppiperidin-3-ol, 190) (2R,3S)-2-((E)-3-(6-(3-chloropheny1)-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 191) (2R,3S)-24(E)-3-(6-(3-fluoropheny1)-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 192) (2R,3S)-24(E)-3-(6-(3-(trifluoromethyl)pheny1)-1H-benzo[d]imidazol-1-ypprop-1-enyl)piperidin-3-ol, 193) (2R,3S)-2-((E)-3-(5-bromo-6,7-ditluoro-2-methy1-1H-benzo[d]imidazol-1-2 0 yl)prop-1-enyl)piperidin-3-ol, 194) (2R,3S)-2-((E)-3-(indolin-l-yl)prop-1-enyl)piperidin-3-ol, 195) (2R,3S)-24(E)-3-(5-chloroindo1in-1-yl)prop-1-enyl)piperidin-3-ol, 196) (2R,3S)-2-((E)-3-(1H-pyrro1o[2,3-b]pyridin-l-yl)prop-1-enyl)piperidin-3-ol, 197) (2R,3S)-2-((E)-3-(6-chloro-1H-indo1-1-y1)prop-1-enyl)piperidin-3-ol, 198) (2R,3S)-2-((E)-3-(6-chloro-1H-indazol-1-y1)prop-1-enyppiperidin-3-ol, 199) (2 R,3S)-2-((E)-3-(4-ch1oro-7H-pyn-olo[2,3-d]pyrimidin-7-yl)prop-1-enyl)piperidin-3-ol, 200) (2 R,3S)-2-((E)-3-(5-chloro-1H-pyrazolo1-3,4-b]pyridin-l-y1)prop-1-enyl)piperidin-3-ol, 201) (2 R,3S)-2-((E)-3-(3,5-dimetliy1-1 H- indazol-1-y1 )prop-1-enyl)piperidin-3-o1, 202) methyl 7-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)- 1H-indole-3-carboxylate, 203) 7-bromo-14(E)-34(2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1 H-indole-3-carboxylic acid, 204) 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid, 205) 4-chloro-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid, 206) 6-chloro-1-4E)-342R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-1 0 carboxylic acid, 207) 7-chloro-1-((E)-3-((2R,3 S)-3-hydroxypiperidin-2-ypally1)-1H-indole-3-carboxylic acid, 208) 6-fluoro-14(E)-34(2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid, 209) 14(E)-342R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid, 210) methyl 4-chloro-1-4E)-342R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylate, 211) methyl 6-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylate, 212) methyl 7-chloro-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-carboxyl ate, 213) methyl 5-bromo-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-carboxylate, 214) methyl 6-bromo-14(E)-3-((2 R,3S)-3-hydroxypiperidin-2-yl)al ly1)-1H-indole-3-2 5 carboxyl ate, 215) 5-bromo-1-((E)-3-((2R,3 S)-3-hydroxypiperidin-2-yl)ally1)-N-methyl-1H-indole-3-carboxam ide, 216) 5-bromo-1-4E)-3-((2R,3S)-3-hydroxypiperidin-2-y1)ally1)-N,N-dimethyl- I H-indole-3-carboxamide, 217) (2R,3 S)-2-((Z)-3-(5-chloro-4-methy1-1H-benzo[d]imidazol-1-y1)-2-fi uoroprop-1-enyl)piperidin-3-ol, 218) (2R,3S)-24(Z)-3-(5-bromo-4-methy1-1H-benzo[d]imidazol-1-y1)-2-fluoroprop-1-enyl)piperidin-3-ol, 219) (2R,3S)-2-((Z)-3-(5,6-dich1oro-1H-benzo[d]im idazol-1-y1)-2-fluoroprop-1-enyl)piperidin-3-ol, 220) (2R,3S)-24(Z)-3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzo[d]imidazol- l -y1)-2-fluoroprop-1-enyl)piperidin-3-ol, 221) (2R,3S)-2-((E)-3-(5-chloro-4-methy1-1H-benzo[d]imidazol-1-y1)-2-mcthylprop-1-enyl)piperidin-3-ol, 222) (2R,3S)-2-((E)-3-(5-bromo-4-methy1-1H-benzo[d]imidazol-1-y1)-2-methylprop-I-enyl)piperidin-3-ol, 223) (2R,3S)-2-((E)-3-(5,6-dich1oro-1H-benzo[d]imidazol-1-y1)-2-inethylprop-1-enyl)piperidin-3-01, 224) (2R,3S)-2-((E)-3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzo[d] imidazol-1-y1)-1 5 2-methylprop-1-enyl)piperidin-3-ol, 225) (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-ynyl)piperidin-ol, 226) (2R,3S)-2-(3-(5-broino-4-methyl-1H-benzo[d]imidazol-1-y1)prop-1-yrtyl)piperidin-3-ol, 227) (2R,3S)-2-(3-(5-chloro-4-methy1-1H-benzo[d]imidazol-1-y1)prop-1-ynyl)piperidin-3-ol, 228) (2R,3S)-2-(3-(5,6-dibromo-1H-benzo[d]imidazol-1-y1)prop-1-ynyl)piperidin-ol, 229) (2R,3S)-2-(3-(5-tluoro-4-methyl-1H-benzo[d] im 1-25idazol-1-yl)prop- ynyl)piperidin-3-ol, and 230) (2R,3S)-2-((E)-3-(5,6-dichloro-1H-benzo[d]imidazol-1-y1)prop-1-enyl)pyrrolidin-3-ol.
In addition, the compounds of the present invention may exist in the form of a pharmaceutically acceptable salt. As salt, an acid addition salt formed by a pharmaceutically acceptable free acid is usefirl. As the free acid, an inorganic acid and an organic acid may be used.
Examples of the inorganic acid may include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like. Examples of the organic acid may include citric acid, acetic acid, lactic acid, maleic acid, gluconic acid, niethanesulfonic acid, succinic acid, 4-toluene sulfonic acid, glutamic acid, aspartic acid or the like.
Salts or solvates of the compounds represented by Chemical Formula 1 that are pharmaceutically not acceptable can be used as intermediates in the preparation of the compound represented by Chemical Formula I, a pharmaceutically acceptable salt or solvate thereof.
The compound represented by Chemical Formula I according to the present invention includes pharmaceutically acceptable salts thereof as well as both solvates and hydrates which can be prepared therefrom. The salts or solvates of the compound represented by Chemical Formula 1 can be prepared from the compounds represented by Chemical Formula 1 using conventional methods in the technical field to which the present invention pertains.
Further. the compound represented by Chemical Formula I according to the present invention can be prepared in crystalline form or non-crystalline form. When the compound represented by Chemical Formula 1 is produced in crystalline form, it may be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by Chemical Formula 1 but also compounds containing a various amount of water.
The solvates of the compound represented by Chemical Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
The present invention also provides a method for preparing a compound represented by Chemical Formula I as shown in the following Reaction Scheme 1:
[Reaction Scheme 1]

al 0, R"

- - ________________________________________________ L
N ______________ L N N 411 x _______________________________________ (Step 1) R' R' 1-C

, HO
/
(Step 2) (in Reaction Scheme 1, n, L, X1, X2 and A are as previously defined, X is halogen (preferably bromo), and R. and R" means each independently a protecting group.
The protecting group can be tert-butyldimethylsilyl, or tert-butyloxycarbonyl.) The step 1 is a step of preparing a compound represented by Chemical Formula 1-C by reacting a compound represented by Chemical Formula 1-A with a compound represented by Chemical Formula 1-B in the presence of a base. Conventional inorganic bases and organic bases can be used as the base. Non-limiting examples of the organic bases may include diisopropylethylamine or triethylarnine. Non-limiting examples of the inorganic bases may include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, or calcium carbonate. Further, the reaction may be carried out in a polar solvent such as methanol, ethanol, butanol, tetrahydroffiran, acetone, toluene, dimethylformamide, dimethylfonnsulfoxide, chloroform, dioxane, acetonitrile diethyl ether, or dichloromethane at 20 C to 150 C for 10 minutes to 24 hours.
The step 2 is a step of preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 1-C in the presence of an acid. Non-limiting examples of the acid may include hydrochloric acid, bromic acid, hydrofluoric acid, trifluoroacetic acid or the like. Preferably, the reaction solvent may or may not use a polar organic solvent. Preferably, when using a polar organic solvent, dichloromethane, chloroform, toluene, dimethylfomiarnide, dioxane, tetrahydrofiiran or the like may be used, and the reaction can be carried out at 20 C to 100 C for 10 minutes to 6 hours.
As another example, the compound represented by Chemical Formula 1-1 can be prepared as shown in the following Reaction Scheme 2:
[Reaction Scheme 2]

F
0, R"

__________________________________________________ L
N (Step 1') R' R' N _________________________________________________________________________ (Step 2') L N 4111 (Step 3') R' (in Reaction Scheme 2, n, L, R2, and A are as previously defined, and R' and R-means each independently a protecting group. The protecting group can be tert-butyldimethylsilyl, or ten-butyloxycarbonyl.) The step 1. is a step of preparing a compound represented by Chemical Fommla 2-C by reacting a compound represented by Chemical Formula 2-A with a compound represented by Chemical Formula 2-B in the presence of a base. Conventional inorganic bases and organic bases can be used as the base. Non-limiting examples of the organic bases may include diisopropylethylamine or triethylamine. Non-limiting examples of the inorganic bases may include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, cesium carbonate, or calcium carbonate. Further, the reaction may be carried out in a polar solvent such as methanol, ethanol, butmol, tetrahydrofuran, acetone, toluene, dimethylformamide, dimethylfonnsulfoxide, chloroform, dioxane, aectonitrile diethyl ether, or dichlorornethane at 20 C
to 150 C for 10 minutes to 24 hours.
The step 2 is a step of preparing a compound represented by Chemical Formula 2-D by reacting an amine group and a nitro group of the compound represented by Chemical Formula 2-C to form a ring. The above step is mined out substantially in two stages.
First, a compound represented by Chemical Formula 2-C is reacted with hydrogen in the presence of Raney nickel and then reacted with trimethyl orthoforrnate. The former reaction is carried out in a polar solvent such as methanol, ethanol, butanol, tetrahydrofuran, acetone, toluene, dimethylformainide, dimethylformsulfoxide, chloroform, dioxane, acetonitrile diethyl ether, or dichloromethane at 20 C to 150 C for 10 minutes to 24 hours. The latter reaction is preferably carried out in the presence of para-toluene sulfonic acid, and the reaction may be carried out in a polar solvent such as methanol, ethanol, butanol, tetrahydrotUran, acetone, toluene, dimethylformamide, dimethylformsulfoxide, chloroform, dioxane, acetonitrile diethyl ether, or dichloromethane at C to 150 C for 10 minutes to 24 hours.
The step 3' is a step of preparing a compound represented by Chemical Formula 1-1 by reacting a compound represented by Chemical Formula 2-D in the presence of an acid. The 15 specific reaction conditions of the step 3' can be applied similarly to the reaction conditions of the step 2 of Reaction Scheme I described above.
Further, as an example, among the compoUnds of Chonical Formula 2-A shown in Reaction Scheme 2, a compound where L is ethylene and R2 is hydrogen (a compound 20 represented by the following Chemical Formula 3) can be prepared by a method as shown in the following Reaction Scheme 3:
[Reaction Scheme 3]

0, oõ.
0, N
Step 1" 3-8 Step 2" /
/ R' R' 0 R' 0, H
N
Step 3" / Step 4" N OH
R' 3-E Step 5" N
Br R' 0 R' t)--/

Step 6" R' 3-G Step 7"
R' (in Reaction Scheme 3, n is as previously defined, and R' and R" means each independently a protecting group. The protecting group can be tert-butyldimethylsilyl, or tert-butyloxycarbonyl.) The step 1" is a step of preparing a compound represented by Chemical Formula 3-B by reacting the compound represented by Chemical Formula 3-A with (carbethoxymethylene) triphenylphosphorane. Preferably, the compound represented by Chemical Formula 3-A is first reacted with oxaly1 chloride and then reacted with triphenylphosphorane. The former reaction is preferably carried out in the presence of methylene chloride, N,N-dimethylsulfoxide, and triethylamine. The former reaction may also be carried out at -78 C to 20 C
for 10 minutes to 12 hours. Further, in the reaction with triphenylphosphorane, dichloromethane may be used as the solvent, and the reaction can be carried out at 20 C to 150 C for 10 minutes to 24 hours.
The step 2- is a step of preparing a compound represented by Chemical Formula 3-C by hydrogenating the compound represented by Chemical Formula 3-B. Preferably, the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst (e.g., palladium hydroxide).
In addition, tetrahydrofuran can be used as a solvent for the reaction.
Further, the reaction can be carried out at 20 C to 150'C for 10 minutes to 24 hours.
The step 3" is a step of preparing a compound represented by Chemical Formula 3-D by hydrolyzing the compound represented by Chemical Formula 3-C. Preferably, the reaction can be carried out under a basic condition, and sodium hydroxide may be used as the base. In addition, water or methanol may be used as a solvent for the reaction. Further, the reaction can be carried out at 20 C to 150 C for 10 minutes to 24 hours.
The step 4" is a step of preparing a compound represented by Chemical Formula 3-E by subjecting the compound represented by Chemical Formula 3-D to a carbonyl reduction reaction.
Preferably, the reaction may be Carried out in the presence of lithium aluminum hydride. In addition, tetrahydrotUran can be used as a solvent for the reaction. Further, the reaction can be carried out at -78 C to 20 C for 10 minutes to 12 hours.
The step 5" is a step of preparing a compound represented by Chemical Formula 3-F by brominating the compound represented by Chemical Formula 3-F. Preferably, the reaction is carried out in the presence of triphenylphosphine and tetrabromomethane. In addition, methylene chloride can be used as a solvent for the reaction. Further, the reaction may be carried out at 20 C
to 150 C for 10 minutes to 24 hours.
The step 6" is a step of preparing a compound represented by Chemical Formula 3-G by subjecting the compound represented by Chemical Formula 3-F to an azide reaction. Preferably, the reaction is carried out in the presence of sodium azide. In addition, N,N-dimethylformarnide can be used as a solvent for the reaction. Further, the reaction may be carried out at 20 C to 150 C
for 10 minutes to 24 hours.
The step 7" is a step of preparing a compound represented by Chemical Formula 3 by aminating the compound represented by Chemical Formula 3-G. Preferably, the reaction is carried out in the presence of triphenylphosphine. In addition, tetrahydrofurari can be used as a solvent for the reaction. Further, the reaction can be carried out at 20 C to 150 C for 10 minutes to 24 hours.
Further, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases caused by abnormality in a PRS (prolyl-tRNA
synthetase) activity, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof The compound represented by Chemical Formula 1 according to the present invention can inhibit PRS enzymatic activity and thus can be used for the prevention or treatment of diseases caused by abnormality in a PRS (prolyl-tRNA synthetase) activity. Examples of diseases caused by abnormality in the PRS (prolyl-tRNA synthetase) activity may include, a cancer, an inflammatory disease, an autoimmune disease and a fibrosis.
As shown in Examples which will he described below, the compound represented by Chemical Formula I according to the present invention can significantly inhibit PRS enzymatic activity and also inhibit the growth of cancer cells. Thus, this compound may be effectively used for the prevention or treatment of the diseases.
The pharmaceutical composition according to the present invention can be formulated in types for oral or parenteral administrations according to a standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carrier, adjuvant or diluent in addition to the active ingredient. Suitable carriers may include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate, and the diluent may include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose andior glycine, but are not limited thereto. Further, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are usually used for the preparation of injectable solutions. In addition, the compounds of the present invention may be formulated as ointments or creams for topical application.
A preferred dose of the compound represented by Chemical Formula 1 according to the present invention may he varied depending on the condition and weight of a patient, the severity of a disease, the type of a drug, and the route and duration of administration, but it may be suitably selected by those skilled in the art. In order to achieve the desirable effects, however, the compound represented by Chemical Formula 1 according to the present invention may be administrated daily at a dose of 0.0001 to 100 mg/kg (body weight), and preferably 0.001 to 100 mg/kg (body weight). The administration may be pei ______________________ formed once a day or in divided doses each day through an oral or parenteral route.
Depending on the method of administration, the pharmaceutical composition according to the present invention may contain the compound represented by Chemical Fonnula 1 or a pharmaceutically acceptable salt thereof in an amount of 0.001 to 99% by weight, preferably 0.01 to 60% by weight The pharmaceutical composition according to the present invention may be administered to mammals such as a rat, a mouse, a domestic animal, a human or the like, through various routes. The administration may be carried out through all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intra-endometrial, intracerebroventneular injection.
ADVANTAGEOUS EFFECTS
The compound represented by Chemical Formula 1 according to the present invention can inhibit PRS enzymatic activity and thus may be effectively used for the prevention or treatment of diseases caused by abnormality in a PRS (prolyl-tRNA synthetase) activity, for example, cancers, inflammatory diseases, autoimmune diseases and fibrosis.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Below, the present invention will be described in more detail by way of examples.
However, these examples are provided only for illustration of the present invention, and should not be construed as limiting the scope of the present invention to these examples.
Example 1: Preparation of (2R33S)-2-(3-(6-chloro-1H-benzoldjimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,s0H

Cl Step 1-1: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(E)-3-ethoxy-3-oxoprop- 1 -en-l-yl)piperidine- I -carboxylate Methylene chloride (47 mL, 0.12 M) and oxalyl chloride (1.0 mL, 11.6 mmol) were added to a flask filled with nitrogen and the reaction solution was cooled to -78 C. N,N-dimethylsulfoxide (1.7 mL, 23.2 mmol) was then added at the same temperature and stirred for 30 minutes. Then, tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1-carboxylate (2.0 g, 5.8 mmol) was dissolved in a small amount of methylene chloride and slowly added. After stirring at the same temperature for 1 hour, triethylamine (3.3 mL, 23.2 mmol) was added and the temperature of the reaction solution was raised to room temperature from -78 C. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried with magnesium sulfate, filtered and concentrated under reduced pressure, and then dissolved in methylene chloride (47 mL, 0.12 M).
(Carbethoxymethylene)triphenylphosphorane (4.0 g, 11.6 mmol) was added thereto at room temperature and stirred for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. "Fhe organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 4:1) to give the title compound (2.1 g, 89% yiekl over two steps).
Step 1-2: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-ethoxy-3-oxopropyppiperidine-l-carbo xyl ate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(E)-3-ethoxy-3-oxoprop- 1 -en-1-yl)piperidine- 1 -earboxylate (3.2 g, 7.7 mmol) obtained from Step 1-1 was dissolved in tetrahydrofuran (50 mL, 0.15 M), and then palladium hydroxide (104 mg, 0.77 mmol) was added thereto. After connection a hydrogen balloon, the mixture was stirred at room temperature for 5 hours. When the reaction was completed. the reaction solution was filtered through celite and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 1 -3 : Preparation of 3-((2R,3S)-I -(tert-butoxycarbony1)-3-(tert-WO 2018/1-17626 PCl/KR2018/001625 butyldimethylsilypoxy)piperidin-2-yl)propenoic acid Tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-ethoxy-3-oxopropyl)piperidine-1 -carboxylate (3.0 g, 7.2 mmol) obtained from Step 1-2 was dissolved in methanol (20 mL, 0.36 M), and then 2N aqueous sodium hydroxide solution (10 mL) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction solution was neutralized with IN aqueous hydrochloric acid solution, acidified and then diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 1-4: Preparation of tert-butyl (2R,35)-3- ((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyppiperidine-1-carboxylate 3-((2R,3S)-1-(tert-butoxyearbony1)-3-(tert-butyldimethylsilypoxy)piperidin-2-yl)propenoic acid (1.6 g, 4.0 mmol) obtained from Step 1-1 was dissolved in tetrahydrofuran (50 mL, 0.08 M), and the reaction solution was cooled to 0 C. Then, a lithium aluminum hydride solution (1.6 mL, 4.0 mmol) was slowly added thereto, reacted at the same temperature for 30 minutes and then stirred at room temperature for 2 hours. A small amount of water was added to complete the reaction, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (diehloromethane:
methanol = 10:1) to give the title compound (1.3 g, yield: 85%).
Step 1-5: Preparation of tert-butyl (2R,3S)-2-(3-bromopropy1)-3-((tert-butyldimethylsilypoxy)piperidine-l-earboxylate Tert-butyl (2R,3S)-3- ((tert-butyldimethylsilypoxy)-2-(3-hydroxypropyl)piperidine-1-carboxylate (5.1 g, 13.8 mmol) obtained from Step 1-4 was added to methylene chloride (100 mL, 0.14 M). The reaction solution was cooled to 0 C, and then triphenylphosphine (4.3 g, 16.5 mmol) and tetrabromomethane (5.5 g, 16.5 mmol) were sequentially added at the same temperature, followed by stirring at room temperature for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure, and purified by column chromatography (hexane: ethyl acetate = 5:1) to give the title compound (4.6 g, yield: 76%).
Step 1-6: Preparation of tert-butyl (2R,3S)-2-(3-azidopropy1)-3-((tert-butyldimethylsily0oxy)piperidine-1-carboxylate Tert-butyl (2R,3S)-2-(3-bromopropy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (7.4 g, 17.0 inmol) obtained from Step 1-5 was dissolved in N,N-dimethylformamide (25 mL, 0.67 M). Then, sodium azide (3.3 g, 17.0 mmol) was added thereto and the mixture was stirred at room temperature for 4 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and then concentrated under reduced pressure, and purified by column chromatography (hexane: ethyl acetate ¨ 7:1) to give the title compound (5.8 g, yield 85%).
Step 1-7: Preparation of tert-butyl (2R,3S)-2-(3-aininopropy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-earboxylate Tert-butyl (2R,3S)-2-(3-azidopropy1)-3 -((tert-b utyldimethyl si lyl)o xy)piperidine-1-carboxylate (5.5 g, 13.8 mmol) obtained from Step 1-6 was dissolved in tetrahydrofuran (24 mL, 0.57 N4), and then triphenylphosphine (4.3 g, 16.5 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, water (24 mL, 0.57 M) was added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and then concentrated under reduced pressure, and purified by column chromatography (dichloroinethane: methanol= 10:1 + niethylamine 2%) to give the title compound (4.0 g, yield: 78%).
Step 1-8: Preparation of tert-butyl (2R,35)-3-((tert-butyldimethylsilyfloxy)-2-(3-((4-ehloro-2-nitrophenyl)am ino)propyl)piperidine--1-carboxylate 3 0 Tert-butyl (2R,3S)-2-(3-aminopropy1)-3-((tert-butylditnethylsilyl)oxy)piperidine-1 earboxylate (1.0 g, 2.7 mmol) obtained from Step 1-7 was dissolved in N,N-dimethylforrnamide (25 mL, 0.67 M). 4-Chloro-2-fluoro- 1-nitrobenzene (518 mg, 3.0 mmol) and N,N-diisopropyl ethylamine (0.93 mL, 5.4 mmol) were then added thereto, and the mixture was heated and stirred at 60 C for 2 hours. When the reaction was completed, the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and and purified by column chromatography (hexane: ethyl acetate = 5:1) to give the title compound (1.2 g, yield:
87%). =
Step 1-9: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(5-chloro-1H-benzo[d]imidazol-1- yl)propyl)piperidine-l-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(344-chloro-2-nitrophenyl)amino)propyl)piperidine-1 -carboxylate (2.6 mg, 4.9 mmol) obtained from Step 1-8 was dissolved in methanol (25 mL, 0.2 M), and then an appropriate amount of Rainy nickel was added thereto. After connecting a hydrogen balloon, the mixture was stirred at room temperature for 1 hour. When the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure. The concentrated compound was dissolved in toluene (30 mL, 0.16 M), and then trimethyl orthofonnate (1.6 mL, 14.6 mmol) and paratoluene sulfonic acid (168 mg, 0.98 mmol) was added thereto, followed by heating and stirring at 50 C for 6 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and and purified by column chromatography (hexane: ethyl acetate ¨ 1:1) to give the title compound (1.8 g, yield: 74%).
Step 1-10: Preparation of (2 R,3 S )-2-(3-(6-chloro- I H-benzo[d]im idazol-1-yl )propyl)piperidi n-3-ol dihydrochloride Tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-(5-chloro-1H-benzo[d]imidazol-1-yppropyppiperidine-1-carboxylate (1.8 g, 3.6 mmol) obtained from Step 1-9 3 0 was dissolved in a small amount of tetrahydrofuran. 4N hydrogen chloride dioxane solution (30 mL, 0.12 M) was then added thereto, and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved by addition of a small amount of methanol, and then crystallized with diethyl ether to give the title compound (1.1 g, yield:
81%).
1H-NMR (500 MHz, Me0D) : 6 9.56 (s. 11-1), 8.18 (d, 1H), 7.86 (d, 1H), 7.70 (dd. 11-1), 4.58 (t, 2H), 3.58 (in, 2H), 2.99 (m, 2H), 2.21 (m, 2H), 2.07 (m, 2H), 1.97 (m, 1H), 1.75 (in, 2H), 1.58 (m, 1H) Example 2: Preparation of (2Ft,3S)-2-(3-(4-bromo-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride ,,OH
N Br H HCI HCI
The title compound (15 mg, yield: 93%) was obtained in the same manner as in Example 1, with the exception that 1-bromo-3-fluoro-2-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example I.
H NMR (500MHz, Me0D): 9.63(s, 1H), 8.02(d, 11-1), 7.86(d, 1H), 7.59(t, 1H), 4.61(t, 2H), 3.56(m, 2H), 3.46(m, I H), 3.27(m, I H), 2.95(m, 2H), 2.20(m, 2H), 2.03(m, 2H), 1.98(m, 1H), 1.78(m, 2H), 1.53(m, 1H) Example 3: Preparation of (212,3S)-2-(3-(5-bromo-1H-benzoldlimidazol-1-2 0 yl)propyl)piperidin-3-ol dihydrochloride N N
H HCI HCI Br The title compound (13 mg, yield: 91%) was obtained in the same manner as in Example 1, with the exception that 4-bromo-1-fluoro-2-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example I.
NMR (500MHz. Me0D): 6 9.53(s, 11-1), 8.08(d, 1H), 7.98(d, 1H), 7.83(dd, 1H), 4.63(t, 2H), 3.74(t, 1H), 3.67(m, 1H), 3.58(m, 2H), 2.97(m, 2H), 2.30(m, 2H), 2.14(m, 2H), 2.02(m, I H), 1.78(m, 2H), 1.55(in, 1H) Example 4: Preparation of (2112,3S)-2-(3-(6-bromo-1H-benzoldlimidazol-1-yflpropyflpiperidin-3-ol dihydrochloride N N
H HCI HCI
Br The title compound (10 mg, yield: 90%) was obtained in the same manner as in Example 1, with the exception that 4-bromo-2-fluoro-l-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example I.
1H NMR (500MHz, Me0D): 9.51(s, IH), 8.32(s, 1H), 7.81(m, 2H), 4.59(t, 2H), 3.58(m, 1H), 2.97(m, 2H), 2.20(m, 2I-1), 2.12(m, 2H), 2.02(m, 1H), 1.79(rn, 2H), 1.59(m, I H) Example 5: Preparation of (212,3S)-2-(3-(7-bromo-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride N N
HCI HCI
Br The title compound (14 mg, yield: 93%) was obtained in the same manner as in Example 1, with the exception that I -bromo-2-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
NMR (500MHz, Me0D): 9.59(s, I H), 7.89(dd, 2H), 7.56(t, 1H), 3.59(m, 111), 2.98(m, 2H), 2.30(m, 2H), 2.13(m, 2H), 2.04(m, 1H), 1.79(m, 2H), 1.56(m, 1H) Example 6: Preparation of (2R,3S)-2-(3-(4-fluoro-1H-betrioldlimidazol- I-yflpropyl)piperidin-3-ol dihydrochloride N F
N
HCI HCI
The title compound (13 mg, yield: 92%) was obtained in the same manner as in Example 1, with the exception that 1,3-difluoro-2-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
1H NMR (500MHz, Me0D): 6 9.52(s, 1H), 7.82(d, 1H), 7.65(m, 11-1), 7.44(m, 114), 4.61(t, 2H), 3.66(m, 1H), 3.58(m, 1H), 3.27(m, I H), 2.97(m, 2H), 2.24(m, 2H), 2.08(m, 2H), 2.02(m, 11-1), 1.75(m, 2H), 1.54(m, 1H) Example 7: Preparation of (2 Rõ.3S)-2-(3-(5-fluoro-1H-benzo[d limidazol- 1-yl)propyl)piperidin-3-ol dihydrochloride N
HCI HCI
The title compound (11 mg, yield: 90%) was obtained in the same manner as in Example 1, with the exception that 1,4-difluoro-2-nitrobenzene was used instead of 4-chloro-2-tluoro- 1 -nitobenzene in Step 1-8 of Example 1.
NMR (500MHz, Me0D): 6 9.56(s, 11-1), 8.07(m, 11-1), 7.65(d, 11-1), 7.50(t, I
H), 4.63(in, 21-1), 3.58(m, 1H), 3.00(m, 2H), 2.24(m, 2H), 2.12(m, 214), 2.02(m, 1H), 1.74(m, 2H), 1.54(m, 1H) Example 8: Preparation of (2 R,3S)-2-(3-(6-tluoro- 11-1-benzoldl imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N N
HCI HCI
The title compound (12 mg, yield: 91%) was obtained in the same manner as in Example 1, with the exception that 2,4-ditluoro- 1 -nitrobenzene was used instead of 4-chloro-2-fluoro- l -nitobenzene in Step 1-8 of Example 1.
IF1 NMR (500MHz, Me0D): 6 9.56(s, 1H), 7.89(m, 2H), 7.48(t, 1H), 4.59(m, 2H), 3.57(m, IF1), 3.03(m, 2H), 2.29(m, 21-I), 2.11(m, 2H), 2.03(m, 1H), I .76(m, 2H). 1.54(m, 1H) Example 9: Preparation of (2R,3S)-2-(3-(7-fluoro-1H-bettio[dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N N
HCI HCI
The title compound (10 mg, yield: 90%) was obtained in the same manner as in Example 1, with the exception that 1,2-difluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
11-1 NMR (500MHz, Me0D): 6 9.57(s, 1H), 7.68(m, 11-1), 7.63(m, 11-1), 7.46(rn, 1H), 4.69(t, 2H), 3.58(m, 1H), 3.25(m, 1H), 2.97(m, 2H), 2.30(m, 2H), 2.15(m, 2H), 2.03(m, 1H), 1.75(m, 2H), I.54(m, 1H) Example 10: Preparation of (2R,3S)-2-(3-(4-eh1oro-1H-benzoldlimidazol-1-1 0 .. yl)propyl)piperidin-3-ol dihydrochloride õOH
Cl N
HCI HCI
The title compound (11 mg, yield: 91%) was obtained in the same manner as in Example 1, with the exception that 1-chloro-3-fluoro-2-nitrobenzene was used instead of 4-chloro-2-1-luoro-1-nitobenzene in Step 1-8 of Example 1.
'fl NMR (500MHz, Me0D): 6 9.55(s, Hi), 7.96(d, IN), 7.67(d, 1H), 7.63(m, 1H), 4.61(t, 2H), 3.60(m, 1H), 3.34(m, 11-1), 3.00(m, 2H), 2.28(m, 21-1), 2.14(m, 2H), 2.03(m, 1H), 1.75(m, 2H), 1.54(m, 1H) Example 11: Preparation of (2R,3S)-2-(3-(5-ehloro-1H-benzoldlimidazo1-1-yl)propyl)piperidin-3-ol dihydrochloride HCI HCI CI
The title compound (8 mu, yield: 87%) was obtained in the same manner as in Example 1, with the exception that 4-chloro-1-fluoro-2-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
I H NMR (500MHz, Me0D): 6 9.55(s, 1H), 8.03(d, 1H), 7.93(s, 1H), 7.69(d, 1H), 4.61(m, 2H), 3.58(m, 11-1), 3.01(m, 2H), 2.29(m, 2H), 2.09(m, 2H), 2.00(m, 1H), 1.74(m, 2H), 1.52(m, 1H) Example 12: Preparation of (2R3S)-2-(3-(7-chloro-1H-benzo I dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH
HCI HCI
Cl The title compound (10 mg, yield: 90%) was obtained in the same manner as in Example 1, with the exception that 1-chloro-2-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example 1.
NMR (500MHz, Nile0D): 6 9.59(s, 1H), 7.83(d, I H), 7.66(d, 1H), 7.61(d, 1H), 3.59(m, 1H), 3.00(m, 2H), 2.30(m, 2H), 2.16(m, 2H), 2.03(m, 1H), 1.83(m, 2H), 1.55(in, 1H) Example 13: Preparation of (2R3S)-2-(3-(6-methy1-1H-benzo[dJimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride PH
=
HCI HCI

The title compound (14 mg, yield: 85%) was obtained in the same manner as in Example 1, with the exception that 2-fluoro-4-methyl-1-nitrobenzene was used instead of 4-chlom-2-fluoro- I -nitobenzene in Step 1-8 of Example 1.
IF1 NMR (500MHz, Me0D): 6 9.42(s, 1H), 7.83(s, 11-1), 7.73(d, 1H), 7.52(d, 1H), 4.590m, 2H), 3.570m, 1H), 2.950-n, 21-1), 2.59(s, 3H), 2.24(m, 2H), 2.11(m, 21-1), 2.01(m, 1H), 1.74(m, 2H), 1.54(m, 1H) Example 14: Preparation of (2R,3S)-2-(3-(5-methyl-1H-benzo [djimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride HCI HCI
The title compound (12 mg, yield: 82%) was obtained in the same manner as in Example 1, with the exception that 1-fluoro-4-methy1-2-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example 1.
NMR (500MHz, Me0D): 6 9.41(s, 1H), 7.89(d, 1H), 7.65(d, 1H), 7.52(m, 1H), 4.56(m, 2H), 3.360m, 21-1), 2.950m, 2H), 2.66(s, 3H), 2.24(m, 2H), 2.070n 31-1), 1.95(m, 2H), 1.720-n, 1H) Example 15: Preparation of (2R,3S)-2-(3-(6-(trifluoromethyl)-11-1-benzokflimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
HCI HCI

The title compound (17 mg, yield: 92%) was obtained in the same manner as in Example 1, with the exception that 2-fluoro- 1 -nitro-4-(trifluoromethyl)benzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example 1.
11-1 NMR (500MHz, Me0D): 6 9.62(s, 1H), 8.45(s, 1U1), 8.06(d, 1H), 7.95(d, 1H), 4.67(m, 2H), 3.62(m, 1H), 2.980m, 2H), 2.22(m, 2H), 2.08(m, 2H), 2.011)m, 1H), 1.71(m, 21-I), 1.54(m, 1H) Example 16: Preparation of (2R,3S)-2-(3-(7-(trifluoromethyl)-1H-2 0 benzoklIimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride ,OH
H Ha HCI

The title compound (15 mg, yield: 89%) was obtained in the same manner as in Example I, with the exception that 2-fluoro- 1 -nitro-3-(trifluoromethyl)benzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
37 NMR (500MHz, Me0D): 6 9.32(m, 11-1), 8.35(m, 21-I), 7.97(m, 1H), 5.02(m, 1H), 4.89(m, 11-1), 3.77(m, 1H), 3.59(m, 211), 3.01(m, 2H), 2.39(m, 411), 1.78(m, 3H) Example 17: Preparation of (2R,3S)-2-(3-(7-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride H HCI HCI

The tide compound (14 mg, yield: 87%) was obtained in the same manner as in Example 1, with the exception that 2-fluoro- 1 -nitro-3-(trifluorornethoxy)benzene was used instead of 4-chloro-2-fluoro-1-nitoberizene in Step 1-8 of Example 1.
NMR (500MHz, Me0D): a 9.68(s. 1H), 7.87-7.64(m, 31-0, 4.81(m, 3H), 3.59(m, 11-I), 2.99(m, 21-I), 2.24(m, 2H), 2.08(m, 311), 1.77(m, 2H), 1.56(m, 111) Example 18: Preparation of (2R93S)-2-(3-(4-(pyrrolidin-1-y0-1H-benzoldjimidazol-1-yl)propyflpiperidin-3-ol dihydrochloride õOH
HCI HCI
Step 18-1: Preparation of tert-btityl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol- -yl)propy1)-3 -((tert-butyldimethylsi lyl)oxy)piperidine- I -carboxyl ate The title compound (1.7 g, yield: 73%) was obtained in the same manner as in Steps 1-1 to 1-9 of Example 1.
Step 18-2: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(4-(pyrrolidin- I -y1)- I H-benzo[d]imidazol-l-yl)propyl)piperidine-1-carboxylate (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilyl)oxy)pipericline- -carboxylate (100 mg, 0.2 mrnol) obtained in Step 18-1 was dissolved in N,-dirriethylfonTiamide (2 mL, 0.09 M). Pyrrolidine (14 mg, 0.2 mmol), 2,2'-
38 bis(diphenylphosphino)-1,1'-binaphthyl) (25 mg, 0.04 inmol), palladium acetate (II) (5 mg, 0.02 mmol) and cesium carbonate (130 mg, 0.4 mmol) were added thereto, and then stirred in a microwave at 100 C for 30 minutes. When the reaction was completed, it was filtered with celite, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by column chromatography (hexane: ethyl acetate =
1:5) to give the title compound (60 mg, yield: 45%).
Step 18-3: Preparation of (2R,3S)-2-(3-(4-(pyrrolidin- I -y1)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol dihydrochloricle The title compound (10 mg, yield: 90%) was obtained in the same manner as in Step 1-9 of Example I.
'Ft NMR (500MHz, Me0D): 6 9.32(s, I H), 7.45(t, 114), 7.17(d, 1H), 6.76(d, 1H). 4.52(t, 21-I), 3.64(m, 3H), 3.57(m, 11-1), 3.48(m, 1H), 2.92(m, 2H), 2.27(m, IF!), 2.18(m, 4H), 2.11(m, 21-[),2.02(m, 11-1), 1.72(m, 2H), 1.55(m, 1H) Example 19: Preparation of (2R,3S)-2-(3-(4-(piperidin-1-y1)-1H-benzoidlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride HCI HCI
The title compound (15 mg, yield: 96%) was obtained in the same manner as in Example 18, with the exception that piperidine was used instead of pyrrolidine in Step 18-2 of Example 18.
H NMR (500MHz, Me0D): 3 9.05(s. I H), 7.69(d, 1H), 7.53(t, 1H), 7.35(d, 1 F1), 4.52(t, 2H), 3.50(m, 5H), 3.34(m, 11-f), 3.26(m, 11-1), 2.950, 21-1). 2.25(m, 214), 2.09(m, 2F1), 2.02(m, 4H), I .75(m, 4H), 1.53(m, 1H) Example 20: Preparation of (2R,3S)-2-(3-(4-(3-fluoropheny1)-1H-benzo[dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride
39 OH
H HCI HCI
Step 20-1: tert-butyl (2R,3S)-2-(3-(4-brorno-1H-benzo[d] imidazol- I -y1 )propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine- 1-carboxylate The title compound (1.7 g, yield: 73%) was obtained in the same manner as in Steps 1-1 to 1-9 of Example 1.
Step 20-2: tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(4-(3-fluoropheny1)-1H-benzo[d]imidazol-1-y1)propyl)p peridine-l-carboxyl ate Tert-butyl (2R,3S)-2-(3-(4-bromo-IH -benzo[d]im -((tert-l-carboxylate (100 mg, 0.2 mmol) obtained in Step 20-1 was dissolved in N,N-dimethylfortnamide (2 inL, 0.09 M). (3-fluorophenyl)boronic acid (22 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.04 mmol), and 2N
sodium carbonate (0.3 mL, 0.76 mmol) were added thereto, and stirred in a microwave at 130 C
for 45 minutes.
When the reaction was completed, it was filtered with celite, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 1:5) to give the title compound (60 mg, yield:
45%).
Step 20-3: Preparation of (2R,3S)-2-(3-(4-(3-fluoropheny1)-1H-benzo[d]imidazol-yl)propyl)piperidin-3-ol dihydrochloride The title compound (19 mg, yield: 91%) was obtained in the same manner as in Step 1-9 of Example 1.
NMR (500MHz, Me0D): 6 9.57(d, 11-1), 8.03(d, 11-1), 7.77(t, 1H), 7.72(d, 11-1), 7.62(m, I H), 7.49(d, 1H), 7.45(m, 1H), 7.29(t, 1H), 4.66(t, 2H), 3.57(m, 11-1), 2.97(m, 2H), 2.25(m, 2H), 2.140m, 2H), 2.02(m, 1H), 1.75(m, 2H), I .55(m, 1 H) Example 21: Preparation of (2 R,3S)-2-(3-(4-(3-chloropheny1)- 1 H-benzoldlimidazol-l-Apropyl)piperidin-3-ol dihydrochloride OH N CI
H HCI HCI
The title compound (18 mg, yield: 89%) was obtained in the same manner as in Example 20, with the exception that (3-chlorophenyl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 6 9.63(s, 1H), 8.07(d, 1H), 7.79(t, 1H), 7.71(m, 21-1), 7.58(m, 3H), 4.67(t, 2H), 3.60(m, 1H), 2.97(m, 21-1), 2.28(rn, 2H) 2.10(m, 21-I), 2.02(m, 1H), 1.85(m, 2H), 1.55(m, 1H) Example 22: Preparation of (2R,3S)-2-(3-(5-(3-fluoropheny1)-1H-benzold)imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N
H HCI HCI -The title compound (7 mg, yield: 26%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(5-brorno-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1 -carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 6 9.56(s, 1H), 8.11(m, 21-1), 7.98(m, 1H), 7.54(m, 2H), 7.20(m, 1H), 7.16(m,1H), 4.67(m, 21-1), 3.61(m, 2H), 3.03(m, 2H), 2.30(m. 2H), 2.12(m, 2H), 1.98(m, 1H), 1.78(m, 21-1), 1.59(m, 1H) Example 23: Preparation of (2R,3S)-2-(3-(6-(2-fluorophenyl)-1H-benzo[djimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride DH
HCI HCI
/
The title compound (13 mg, yield: 34%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(6-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3 S)-2-(3 -(4-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (2-fluorophenyl)boronic acid was used instead of (3-fluorophertyl)borortic acid in Step 20-2 of Example 20.
IF1 NMR (500MHz, Me0D): 6 7.98(s, 1H), 7.88(m, 1H), 7.71(m, 1H), 7.59(m, 114), 7.44(m, 1H), 7.32(m, 11-1), 7.25(m, 1H), 4.58(m, 21-1), 3.55(m, 1H), 2.94(m, 2H), 2. I 9(m, 2H), 2.06(m, 2H), 2.00(m, 1H), 1.70(m, 2H), 1.53(m, 1H) Example 24: Preparation of (2R33S)-2-(3-(6-(3-fluoropheny1)-1H-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride SDH
HCI HCI
The title compound (11 mg, yield: 30%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(6-brorno-11-1-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y0propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 6 9.27(s, 114). 8. I 8(m, 111), 7.91(m, 211), 7.58(m, 11-1), 7.52(m, 2H), 7.17(t, 1H), 4.65(m, 21-1), 3.57(m, 1H), 2.96(m, 2H), 2.23(m, 2H), 2.08(m, 2H), 2.00(rn, 1H), 1.73(in, 2H), 1.57(m, 1H) Example 25: Preparation of (2R,3S)-2-(3-(6-(4-fluoropheny1)-1H-benzoldlimidazol-1-y0propyl)piperidin-3-ol dihy-drochloride ,OH
=
HCI HCI
The title compound (8 mg, yield: 28%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(6-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsilypoxy)piperidine- I -carboxylate, and that (4-fluorophenyl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
IF1 NMR (500M1-fz, Me0D): 6 7.97(s, 1H). 7.83-7.74(m, 4H), 7.23(m, 2H), 4.55(in, 2H), 3.54(m, 1H), 2.940-n, 2H), 2.20(m, 2H), 2.05(n, 2H), 2.000-n, 11-1), 1.69(m, 2H), 1,53(m, I H) Example 26: Preparation of (2R,3S)-2-(3-(7-(2-fluorophenyl)-1H-1 5 benzoic!' imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
N
HCI HCI
The title compound (11 mg, yield: 30%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily0oxy)piperidine-1-earboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-l-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine- I -carboxylate, and that (2-fluorophenyl)boronic acid was used instead of (3-tluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz. Me0D): 6 9.50(s, IN). 7.94(d, IN), 7.75(t. IF!). 7.62(m, 1H), 7.57(m, 1H), 7.53(d, 1H), 7.43(m, 1H), 7.38(t, 1H), 4.27(m, I H), 4.09(m, I
H), 3.42(m, 1H), 3.16(m, 1H), 2.90(m, 1H), 2.73(m, 1H), 1.97(m, 2H), 1.77-1.62(in, 3H), 1.47(m, 2H), 1.27(m, 11-1) Example 27: Preparation of (2R,3S)-2-(3-(7-(3-fluoropheny))-1 H-bouo id imid azol-1-y0p ropyl)piperidin-3-ol dihydrochloride ,OH
HCI HCI
The title compound (7 ing, yield: 28%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-1H-benzo[d]imidazol- I -yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y0propyl)-3-((tert-butyldimethylsily0oxy)piperidine-1-carboxylate in Step 20-2 of Example 20.
11-1 INA4R (500MHz, Me0D): 6 9.49(s, 11-0, 7.91(d, 1H), 7.72(t, 11-0, 7.59(m, 1H), 7.50(d, 1H), 7.36(m, 3H), 4.17(m, 2H), 3.37(m, 1H), 3.16(m, 1H), 2.90(m, 1H), 2.73(m, 1H), .. 1.96(m, 2H), 1.67(m, 3H), 1.50(m, 2H), 1.32(m, 1H) Example 28: Preparation of (2R,3S)-2-(3-(7-(4-fluoropheny1)-1H-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
HCI HCI
The title compound (13 mg, yield: 32%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-1H-benzo[d]imidazol- I -y0propy1)-3-((tert-butyldimethylsily0oxy)piperidine- I -carboxylate was used instead of tert-butyl (2 R,3S)-2-(3-(4-brorno- 1 H-benzo[d] imidazol- 1 -Apropy1)-3-((tert-butyldimethylsi lypoxy)piperidine- 1-carboxylate, and that (4-fluorophenyl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
H N1MR (500MHz, Me0D): 6 9.48(s, 1H), 7.89(d, 1H), 7.68(t, 1H), 7.54(m, 2H), 7.50(d, 1H), 7.33(t, 211), 4.14(m, 211), 3.42(m, 1H), 3.16(m, 1H), 2.90(m, 1H), 2.72(m, 1H), 1.97(m, 2H), 1.72(m, 31-1), 1.50(m, 21-1), 1.31(in, 1H) Example 29: Preparation of (2R,3S)-2-(3-(5-(1H-pyrazo14-yl)-1H-benzoldlimidazol-1-yppropyl)piperidin-3-o1 dihydrochloride N
HCI HCI \ ' -NH
The title compound (7 mg, yield: 19%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(6-bromo-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate, and that (1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.53(s, 1.11), 8.32(s, 111), 8.07(m, 11-1), 7.70(m, 21-1), 7.58(m, 1H), 4.63(m, 2H), 3.60(m, 1H), 3.00(m, 2H), 2.30(m, 2H), 2.14(m, 2H), 2.05(m, 1H), 1.78(m, 2H), 1.55(m, 1H) Example 30: Preparation of (2R,3S)-2-(3-(6-(1H-pyrazol-4-y1)-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride OH
_N
HCI HCI
/
N-N
The title compound (6 mg. yield: 15%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(6-bromo-1H-benzo[d]im idazol-1-y1)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine- 1 -earboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 7\IMR (500MHz, Me0D): 6 9.52(s, 1H), 8.48(s, 1H), 8.03(d, 111), 7.87(d, 1H), 7.68(m, I H), 7.58(m, 1H), 4.66(m, 2H), 3.60(m, 1H), 2.97(m, 21-i), 2.31(m, 2H), 2.14(m, 2H), 2.00(m, 1H), 1.77(m, 2H), 1.54(m, 1H) Example 31: Preparation of (2R,3S)-2-(3-(7-(1H-pyrazol-4-yl)-1H-benzo[djimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
HCI HCI
HN, The title compound (5 mg, yield: 12%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo- I H-benzokijimidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-1 5 (4-bromo-IH-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-l-carboxylate, and that (11-1-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): d9.55(, 11-1), 7.99(s, 1H), 7.87(d, 1H), 7.69(t, 1H), 7.51(d, 1H), 4.35(m, 2H), 3.50(m, 2H). 3.21(m, 1H), 2.97(m, 1H). 2.77(m, 1H), 2.01(m, 2H), 1.76(m, 2H), 1.70(m, 2H), 1.55(m, 1H), 1.45(m, 1H) Example 32: Preparation of (2R,3S)-2-(3-(6-chloro-5-fluoro-111-benzo[dlimidazol-1-y1)propyppiperidin-3-ol dihydrochloride õOH N

CI
The title compound (25 mg, yield: 83%) was obtained in the same manner as in Example 1, with the exception that 1-chloro-2,5-ditluoro-4-nitrobenzene was used instead of 4-chloro-2-fluoro- 1-nitrobenzene in step 1-8 of Example 1.
11-1-NMR (500 MHz, N4e0D) : 69.55 (s, 1H), 8.33 (d, 11-1), 7.82 (d, 11-1), 4.58 (td, 2H), 3.59 (m, 2H), 2.98 (m, 2H), 2.23 (m, 2H), 2.08 (m, 2H), 1.98 (in, 1H), 1.77 (in, 2H), 1.76 (m, I H) Example 33: Preparation of (2R,3S)-2-(3-(6-bromo-5-fluoro-1H-bertzo[dI
imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH

Br The title compound (15 mg, yield: 81%) was obtained in the same manner as in Example 1, with the exception that 1-bromo-2,5-difluoro-4-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitrobenzene in step 1-8 of Example 1.
I H-NMR (500 MHz, Me0D) : 6 9.55 (s. 1H), 8.46 (d, 1H), 7.79 (d, 11-1), 4.59 (t, 2H), 3.59 (m, 1H), 2.97 (m, 2H), 2.22 (m, 2H), 2.08 (m, 211), 1.97 (m, 1H). 1.76 (m, 2H), 1.56 (in, 114) Example 34: Preparation of (212õ3S)-2-(3-(5-chloro-6-fluoro-1H-benzo[dflmidazol-1-y1)propyflpiperidin-3-ol dihydrochloride N
Cl The title compound (20 mg, yield: 80%) was obtained in the same manner as in Example 1, with the exception that 1-chloro-2,4-difluoro-5-nitrobenzene was used instead of 4-chloro-2-2 0 fluoro-l-nitrobenzene in step 1-8 of Example 1.
H-NMR (500 MHz, Me0D) : 6 9.55 (s, IF{), 8.09 (d, 111), 8.06 (d, III), 4.58 (t, 2H), 3.60 (in, 2H), 2.98 (in, 211), 2.21 (m, 2H), 2.09 (in, 2H), 1.97 (in, 1H), 1.76 (m, 2H), 1.56 (m, I H) Example 35: Preparation of (2R,3S)-2-(3-(5-bromo-6-fluoro-1H-benzo[djimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH N
Br The title compound (22 mg, yield: 83%) was obtained in the same manner as in Example 1, with the exception that 1-bromo-2,4-difluoro-5-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitrobenzene in step 1-8 of Example 1.
1H-NMR (500 MHz, Me0D) : (59.58 (s, 1E0, 8.19 (d, 1H), 8.07 (d. 11-1), 4.58 (t, 2H), 3.59 (m, 2H), 2.98 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.96 (m, I H), 1.76 (m, 2H), 1.56 (m, 1H) Example 36: Preparation of (2R,3S)-2-(3-(6-bromo-5-chloro-11-1-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride _N
Cl Br The title compound (22 mg, yield: 83%) was obtained in the same manner as in Example I, with the exception that 1-bromo-2-chloro-5-fluoro-4-nitrobenzene was used instead of 4-chloro-2-fluoro- l -nitrobenzene in step 1-8 of Example 1.
1H-NMR (500 MHz, Me0D) : 6 9.54 (s, 11-1), 8.51 (s, 11-1), 8.10 (s, 1H), 4.58 (t, 2H), 3.66 (m, 2H), 2.98 (m, 2H), 2.23 (in, 2H), 2.08 (m, 2H), 1.97 (m, IH), 1.76 (m, 2H), 1.56 (m, IN) Example 37: Preparation of (2R,3S)-2-(3-(6-ch1oro-5-methoxy-1H-benzokIlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride o/

Cl The title compound (18 mg, yield: 81%) was obtained in the same manner as in Example 1, with the exception that 1-chloro-5-fluoro-2-methoxy-4-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitrobenzene in step 1-8 of Example 1.
I H-N1R (500 MHz. Me0D) : (59.44 (s, 111), 8.17 (s, 1H). 7.45 (s, I H). 4.56 (t, 2H), 4.02 (s, 3H), 3.58 (t, 1H), 2.98 (m, 2H), 2.21 (m, 2H), 2.05 (m, 2H). 1.97 (In, 1H), 1.76 (m, 2H), 1.54(m, 1H) Example 38: Preparation of (2R,3S)-2-(3-(6-fluoro-5-methoxy-111-benzoicliimidazo1-1-yl)propyl)piperidin-3-ol dihydrochloride o/

The title compound (18 mg, yield: 81%) was obtained in the same manner as in Example 1, with the exception that 1,5-difluoro-2-methoxy-4-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitrobenzene in step 1-8 of Example 1.
'H-NMR (500 MHz, Me0D) : 6 9.45 (s, 114), 7.92 (d. 1H), 7.48 (d. 11-1), 4.55 (t, 2H), 4.00 (s, 31-1), 3.58 (in, 211), 2.99 (m. 211), 2.22 (m, 211), 2.06 (m, 2H), 1.97 (in, 1H), 1.77 (m, 2H) Example 39: Preparation of (2R,3S)-2-(3-(5-fluoro-6-methyl-1H-benzo[dlimidazol-1-yhpropyl)piperidin-3-ol dihydrochloride õOH
/
F

The title compound (15 mg, yield: 79%) was obtained in the same manner as in Example 1, with the exception that 1,4-difluoro-2-methy1-5-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitrobenzene in step 1-8 of Example 1.
tH-NMR (500 MHz, Me0D) : 6 9.49 (s, 111), 7.96 (d. 2H), 7.58 (d, 1H), 4.59 (t, 2H), 3.59 (m, 1H), 3.00 (m, 2H), 2.50 (s, 3H), 2.22 (ni, 2H), 2.08 (m, 2H), 1.97 (m, 11-0, 1.77 (m, 2H), 1.56 (m, 1H) Example 40: Preparation of (2R,3S)-2-(3-(4,5-dichloro-1H-benzoidlimidazol-1-y0propyl)piperidin-3-ol dihydrochloride N
[--- CI
L=..N
CI

The title compound (26 mg, yield: 81%) was obtained in the same manner as in Example 1, with the exception that 1,2-dichloro-4-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitrobenzene in step 1-8 of Example 1.
1H-NMR (500 MHz, Me0D): 6 9.67 (s. 114). 8.02 (d, 111). 7.82 (d, 1H), 4.62 (m, 2H).
3.60 (m, 1H), 3.28 (m, 1H), 2.99 (m, 2H), 2.25 (m, 2H), 2.08 (in, 2H), 1.99 (m, 1H), 1.78 (m, 2H), 1.54 (m, 1H) Example 41: Preparation of (2S,3S)-2-(3-(4,5-dichloro-1H-benzo[dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH HCI N
H HCI
The title compound (19 mg, yield: 85%) was obtained in the same manner as in Example 1, with the exception that tert-butyl (2S,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyl)piperidine-l-earboxylate was used instead of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-hydroxypropyppiperidine- I -carboxylate in Step 1-5 of Example I.
NMR (500MHz, Me0D): 6 9.58(d, IN). 7.97(d, IFI), 7.81(d, IN). 4.59(m, 2H).
4.02(s, 1H), 3.27(s, 1H), 3.20(in, I H), 1H), 2.18-2.05(m, 3H), 1.94(m, I H), 1.87(m. I H), 1.72-1.67(m, 3H) Example 42: Preparation of (2S,3R)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-2 0 yl)propyl)piperidin-3-ol dihydrochloride OH HCI N
ci CI
H HCI
The title compound (33 mg, yield: 84%) was obtained in the same manner as in Example I, with the exception that tert-butyl (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyl)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-hydroxypropyl)piperidine- I -carboxylatc in Step 1-5 of Example 1.
'FT NMR (500IVIHz. Me0D): 6 9.64(d. 111), 8.00(dd, I El). 7.82(d, I H), 4.61(m, 2H), 3.59(m, 1H), 3.27(s, IH), 3.02-2.93(m, 2H), 2.29-2.18(m, 2H), 2.07(in, 2H), I
.99(m, I H), 1.58(m, 2H), 1.51(m, 1H) Example 43: Preparation of (211,3R)-2-(3-(4,5-dichloro-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochlotide OH HCI N
ci CI
H HCI
The title compound (23 mg, yield: 85%) was obtained in the same manner as in Example 1, with the exception that tert-butyl (2R,3R)-3-((tert-butyldimethylsilypoxy)-2-(3-hydroxypropyppiperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxypropyppiperidine-1-carboxylate in Step 1-5 of Example 1.
NMR (500MHz, Me0D): 6 9.66(d, 11-1), 7.97(d, 11-1), 7.83(d, 1H), 4.60(t, 2H), 4.01(s, 1H), 3.27(s, 1H), 3.20(t, 1H), 3.00(t, 1H), 2.20-2.05(m, 3H), 1.94(m, I H), 1.88(m, I H), 1.73-1.66(m, 3H) Example 44: Preparation of (2R,3S)-2-(3-(4-chloro-5-methy1-1H-benzo[dlimidazol-1 5 1-yl)propyl)piperidin-3-ol dihydrochloride CI
N

The title compound (25 mg, yield: 80%) was obtained in the same manner as in Example 1, with the exception that 2-chloro-4-fluoro--1-methy1-3-nitrobenzene was used instead of 4-ch1oro-2-fluoro- -nitrobenzene in step 1-8 of Example 1.
IH-NMR (500 MHz, Me0D): 8 9.61 (s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 4.60 (1, 2H), 3.58 (m, 2H), 2.97 (m, 2H), 2.58 (s, 3H), 2.23 (m, 2H), 2.06 (m, 2H), 1.96 (m, 1H), 1.76 (m, 2H), 1.54(m, 1H) Example 45: Preparation of (2R,3S)-2-(3-(5-bromo-4-methyl-1 1-1-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride I
Br Step 45-1: Preparation of tert-butyl (2R,3S)-2-(3-(5-bromo-4-m ethyl-1H-benzo[d] imidazol-1-y0propyl)-3-(tert-butyld im ethyl si lypoxy)piperidin-l-carboxylate Tert-butyl (2R,3 S)-2-(3 -bromopropy1)-3-((tert-butyldimethylsi I yl)oxy)piperidine-1 -carboxylate (40 mg, 0.09 mmol) obtained from Step 1-5 of Example I was dissolved in N,N-dimethylformamide (2 mL, 0.05 11/1). Then, potassium carbonate (25 mg, 0.18 mmol) and 5-bromo-4-methy1-1H-ben7o[d]imidazole (18 mg, 0.09 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 1:1) to give the title compound (43 mg, yield: 85%).
Step 45-2: Preparation of (2R,3S)-2-(3-(5-bromo-4-methyl- 11 l-benzordlimidazol-1-1 5 yl)propyl)piperidin-3-ol dihydrochloride Tert-buty1(2R,3S)-2-(3-(5-bromo-4-methyl-IH-benzo[d]imidazol-1-y1)propyl)-3-(tert-butyldimethylsilyfloxy)piperidin- 1 -carboxylate (43 mg, 0.08 mmol) obtained from Step 45-1 was dissolved in a small amount of tetrahydrofuran. Then, 4N hydrogen chloride dioxane solution (2.0 mL, 0.04 M) was added, and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved by additio of a small amount of methanol, and then crystallized with diethyl ether to obtain the title compound (27 mg, yield: 85%).
'H-MR (500 MHz, DMSO-d6) : 6 9.19 (s, 1H), 7.82 (d, I H), 7.76 (s, 1H), 4.47 (m, 2H), 3.38 (m, 1H), 3.09 (d, 1H), 2.81 (in, 2H), 2.65 (s, 3H), 2.19 (m, 1H), 2.10 (m, 1H), 1.88 (m, 2H), 1.75 (m, 1H), 1.72 (in, I H), 1.58 (m, 1H), 1.37 (m, 1H) Example 46: Preparation of (21293S)-2-(3-(5-chloro-4-methy1-1H-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N
CI

The title compound (30 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 5-chloro-4-methyl-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
'1-1-NMR (500 MID. Me0D): 8 9.53 (s, 11-1), 7.83 (d, 1H), 7.69 (d, 1H), 4.58 (t, 21-0, 3.58 (m, 1H), 3.28 (m, 1H), 2.96 (m, 2H), 2.70 (s, 3H), 2.22 (m, 211), 2.05 (m, 2H), 2.00 (m, 1H), 1.75 (m, 2H), 1.55 (m, 1H) Example 47: Preparation of (2R,3S)-2-(3-(5-bromo-4-fluoro-1H-benzo[d]imidazol-1 0 1-yl)propyl)piperidin-3-ol dihydrochloride N
N
H 2HCI Br The title compound (10 mg, yield: 40%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-4-fluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): (39.47 (s, 1H), 7.84 (dd, 114), 7.79 (d, 114), 4.60 (m, 2H), 3.59 (m, 114), 3.27 (in, 11-1), 2.99 (in, 2H), 2.20 (m, 2H), 2.07 (m, 2H), 1.98 (in, 1H), 1.75 (m, 2H), 1.56 (m. 1H) Example 48: Preparation of (2R,3S)-2-(3-(6-bromo-7-fluoro-1H-benzo[dlimidazol-2 0 1-yl)propyl)piperidin-3-ol dihydrochloride N
N

Br The title compound (11 mg, yield: 43%) was obtained in the same manner as in Example 45, with the exception that 6-hromo-7-fluoro-11-1-benzo[d]imidazole was used instead of 5-bromo-4-methyl-1H-benzokliim idazole in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): (39.53 (S, 1H), 7.85 (dd, 11-1), 7.64 (d. 1H), 4.67 (in, 214), 3.59 (in, 1H), 3.27 (n, 1H), 2.98 (in, 2H), 2.23 (in, 2H), 2.09 (n, 2H), 1.98 (m, 1H), 1.77 (m, 2H), 1.54(m, 1H) Example 49: Preparation of (2R,3S)-2-(3-(4,5-difluoro-1H-benzo[dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride F

The title compound (9 mg, yield: 39%) was obtained in the same manner as in Example 45, with the exception that 4,5-difluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
'H-NMR (500 MHz, DMSO-d6): 6 8.58 (s, 1H), 7.58 (dd, I H), 7.40 (dd, 1H), 4.33 (m, 2H), 3.38 (n, 1H), 3.09 (d, 1H), 2.98 (in, 2H), 2.10 (in, lip, 1.96 (in, 1E1), 1.87 (n, 21-1), 1.77 (in, 1H), 1.65 (m, 1H), 1.54 (m, I H), 1.36 (m, 1H) Example 50: Preparation of (2R,3S)-2-(3-(6,7-difluoro-1H-benzo[dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride /

The title compound (10 mg, yield: 41 ,/o) was obtained in the same manner as in Example 45, with the exception that 6,7-difluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl- I H-benzo[d]imidazole in step 45-1 of Example 45.
IH-NMR (500 MHz, DMSO-d6): 6 8.94 (s, 1H), 7.59 (dd, 1H), 7.44 (dd, 1H). 4.44 (m, 2H), 3.41 (m, 1H), 3.09 (d, 1H), 2.78 (m, 2H), 2.13 (in, 1H). 2.03 (m, 1H), 1.89 (m, 2H), 1.76 (d, 11-1), 1.66 (n, I H), 1.57 (in, 1H), 1.35 (n, 1H) Example 51: Preparation of (2R,3S)-2-(3-(4,5-dimethy1-1H-benzo[djimidazol-1-2 5 yl)propyl)piperidin-3-ol dihydrochloride õOH

The title compound (30 mg, yield: 86%) was obtained in the same manner as in Example 45, with the exception that 4,5-dimethy1-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, MeOD): 6 9.48 (s, 11-1), 7.71 (d, 1H), 7.51 (d, 11-1), 4.57 (t, 21-1), 3.58 (m, 1H), 3.27 (m, 1H), 2.98 (m, 2H), 2.56 (s, 3H), 2.48 (s, 3H), 2.23 (m, 2H), 2.06 (m, 21-1), 1.98 (m, 1H), 1.76 (m, 2H), 1.55 (in, 1H) Example 52: Preparation of (2R,3S)-2-(3-(5,6-difluoro-1H-benzofdlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride The title compound (32 mg, yield: 84%) was obtained in the same manner as in Example 45, with the exception that 5,6-difluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]irnidazole in step 45-1 of Example 45.
1H-NMR (500 MHz. Me0D): 6 9.58 (s, 1H). 8.17 (dd, 1H), 7.88 (dd, 1H), 4.59 (t, 2H), 3.59 (m, 1H), 3.28 (m, 1H), 2.99 (m, 2H), 2.23 (m, 2H), 2.08 (m, 2H), 1.97 (m, 1H), 1.77 (m, 2H), 1.56(m, 1H) Example 53: Preparation of (2R93S)-2-(3-(5,6-dichloro-IH-benzoldlimidazol-l-2 0 yl)propyl)piperidin-3-ol dihydrochloride CI

CI
The title compound (37 mg, yield: 85%) was obtained in the same manner as in Example 45, with the exception that 5,6-dichloro-11-1-benzo[d]imidaz.ole was used instead of 5-bromo-4-methyl-1H-benzokilimidazole in step 45-1 of Example 45.

1H-NMR (500 MHz, DMSO-d6): 6 9.10 (s, 11-1), 8.08 (s, 1E1), 4.39 (m, 214), 3.41 (in, 1H), 3.10 (m, 1H), 2.80 (m, 2H), 2.11 (m, I H), 2.01 (m, 1H), 1.90 (in, 2H), 1.77 (m, I H), 1.67 (m, I H), 1.57 (m, I H), 1.35 (m, 1 H) Example 54: Preparation of (2R,3S)-2-(3-(5,6-dibromo-1H-benzoldlimidazol-1-y0propyl)piperidin-3-ol dihydrochloride N
Br Br The title compound (31 nig, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 5,6-dibromo- I Fl-benzo[d]imidazole was used instead of 5-bromo-4-methyl-IH-benzo[d]imidazole in step 45-1 of Example 45.
'F{-NMR (500 MHz, DMSO-d6): (38.93 (s, 1K), 8.38 (s, 1H), 8.17 (2, 1H), 4.37 (m, 21-1), 3.40 (m, 1H), 3.10(d, 1H), 2.79 (m, 2H), 2.07 (m, 1H), 1.99 (in, 1H), 1.89 (m, 2H), 1.77 (d, I H), 1.65 (in, 1H), 1.53 (m, 1H), 1.35 (rn, 1H) Example 55: Preparation of (211,3S)-2-(3-(5,6-dimethyl-1H-benzoldjimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride µ,,OH N
f---The title compound (36 mg, yield: 85%) was obtained in the same manner as in Example 45, with the exception that 5,6-dimethy1-1H-benzo[d]imidazole was used instead of 5-bromo-4-2 0 methyl- I H-benzo[d]imidazole in step 45-1 of Example 45.
H-NMR (500 MHz. Me0D): (39.38 (s, 114), 7.80 (s, 1H), 7.62 (s, 1H), 4.59 (in, 214), 3.59 (in, 1H), 3.27 (m, 114), 2.99 (m, 2H), 2.51 (s, 3H), 2.49 (s, 3H), 2.24 (m, 2H), 2.08 (m, 2H), 1.97 (in, 1H), 1.77 (in, 2H), 1.56 (m, 11-I) Example 56: Preparation of (2R,3S)-2-(3-(6,7-dichloro-1H-benzoldlimidazol-l-Apropyl)piperidin-3-ol dihydrochloride N

CI
The title compound (15 mg, yield: 30%) was obtained in the same manner as in Example 45, with the exception that 6,7-dichloro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazo1e in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): 6 9.43 (s, 114), 7.80 (s, 214), 4.83 (rn, 2H), 3.58 (t, 114), 3.28 (m, 1H), 2.99 (m, 2H), 2.21 (rim, 2H), 2.10 (m, 2H), 2.09 (m, 1H), 1.77 (m, 214), 1.76 (m, 1H) Example 57: Preparation of (2R,3S)-2-(3-(4,6-difluoro-1H-benzoldlimidazol-1-yppropyl)piperidin-3-ol dihydroehloride N, HCI HCI

The title compound (26 mg, yield: 92%) was obtained in the same manner as in Example 45, with the exception that 4,6-difluoro- I H-bcrizo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
IH NMR (500MHz, Me0D): 6 9.56(s, 1H), 7.76(d, 1H), 7.39(t, 114), 4.57(m, 2H), 3.62(m, 1H), 2.99(m, 21-1), 2.68(m, I H), 2.28(m, 2H), 2.12(m, 2H), 2.05(m, 1H), 1.80(m, 2H), 1.55(m, 1H) Example 58: Preparation of (2VS)-2-(3-(5,7-difluoro4H-benzokIlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N

The title compound (25 mg, yield: 90%) was obtained in the same manner as in Example 45, with the exception that 4,6-di tluoro- I H-benzo[d]imidazole was used instead of 5-bromo-4-methyl-IH-benzordlimidazole in Step 45-1 of Example 45.
I H NMR (500MHz, Me0D): 6 9.60(d, 1H). 7.51(d, 1H), 7.42(t, 1H), 4.66(m, 2H), 3.58(m, 1H), 2.98(m, 214), 2.30(m, 2H), 2.12(m, 2H), 2.02(m, 1H), 1.74(m, 214), 1.54(m, 1H) Example 59: Preparation of (2R,3S)-2-(3-(4-chloro-5-methoxy-1H-ben2o[d]imidazol-1-yl)propybpiperidin-3-ol dihydrochloride CI

HCI HCI
The title compound (23 mg, yield: 91%) was obtained in the same manner as in Example 45, with the exception that 4-chloro-5-methoxy-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
1H NMR (500MHz, Me0D): 6 9.55(s, 1H), 7.97(d, 114), 7.52(d, 1H), 4.59(t, 2H).
4.04(s, 3H), 3.57(m, 114), 2.99(m, 2H), 2.31(m, 2H), 2.10(m, 2H), 2.02(m, 1H), 1.79(m, 214), 1.55(m, 111) Example 60: Preparation of (2R,3S)-2-(3-(7-chloro-6-methoxy-1H-benzo[d I imidazol-1-yppropyl)piperidin-3-ol dihydrochloride OH FL-A
N
HCI HCI Cl The title compound (22 mg, yield: 90%) was obtained in the same manner as in Example 45, with the exception that 4-chloro-5-inethoxy-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl- 1 H-benzo[d]imidazole in Step 45-1 of Example 45.
114 NMR (500MHz, Me0D): 6 9.48(s, 114), 7.79(d, 1H), 7.52(d, 11-1), 4.82(m, 2H), 4.03(s, 31-1), 3.62(m, I H), 2.99(m, 2H), 2.30(m, 2H), 2.14(m, 21-1), 2.02(m, 1H), 1.80(m, 214), 1.55(m, 1H) Example 61: Preparation of (2R,3S)-2-(3-(6-chloro-4-methyl-1H-benzo[d I
imidazol-1-yl)propyl)pipetidin-3-ol dihydrochloride HCI HCI
CI
The title compound (24 mg, yield: 91%) was obtained in the same manner as in Example 45, with the exception that 6-chloro-4-methyl-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45, 11-1 NMR (500MHz, Me0D): 6 9.59(s, 1H), 7.97(s, 1E1), 7.52(s, 11-1), 4.58(m, 2H), 3.59(m, I H), 2.97(m, 21-1), 2.67(s, 3H), 2.20(in, 2H), 2.10(m, 2H), 2.01(m, 1H), 1.76(m, 2H), I .55(m, 1H) Example 62: Preparation of (2R,3S)-2-(3-(4-chloro-5-fluoro-111-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH
N
CI
/ F
HCI HCI
The title compound (19 mg, yield: 89%) was obtained in the same manner as in Example 45, with the exception that 4-ehloro-5-tluoro-1H-benzo[d]iinidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
'Fl NMR (500MHz, Me0D): 6 9.54(s, 1H), 7.95(d, 11-1), 7.50(d, 11-1), 4.58(t, 21-1).
3.56(rn, 1H), 3.42(m, I H), 2.98(m, 2H), 2.30(m, 2H), 2.08(m, 2H), 2.00(in, 1H), 1.72(m, 2H), 1.52(m, 1H) Example 63: Preparation of (2R,3S)-2-(3-(6-bromo-4-methyl-1H-benzoldjimidazol-l-yl)propyl)piperidin-3-ol dihydrochloride õOH
HCI HCI
Br The title compound (26 mg, yield: 93%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-4-methyl-1H-benzoidlimidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]im idazole in Step 45-1 of Example 45.

11-1 NMR (500MHz, Me0D): 6 9.58(s. 11-1). 8.12(s, 1i-f), 7.66(s, 111), 4.57(m, 211), 3.60(m, 1H), 2.99(m, 2H), 2.65(s, 3H), 2.24(m, 2H), 2.10(m, 214), 2.02(m, 1H), 1.79(m, 2H), 1.59(m, 114) Example 64: Preparation of (2R,3S)-2-(3-(5-tluoro-4-methyl-1.1-1-benzoldlimidazol-l-yl)propyl)piperidin-3-ol dihydrochloride N
N
HCI HCI
The title compound (22 mg, yield: 90%) was obtained in the same manner as in Example 45, with the exception that 5-fluoro-4-methyl-1H-benzo[d]imidazole was used instead of 5-in Step 45-1 of Example 45.
NMR (500MHz, Me0D): 6 9.62(s, 114), 7.88(dd, 11-1), 7.46(t, 1H), 4.61(m. 21-1), 3.58(m, 1H), 2.99(m, 2H), 2.59(s, 314), 2.25(m, 2H), 2.12(m 2H), 2.01(m, 114), I.79(m, 2H), 1.59(m, 1H) Example 65: Preparation of (2R,.3S)-2-(3-(6-fluoro-7-methyl-1H-benzo[dlintidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,,OH
N
HCI HCI
The title compound (20 mg, yield: 88%) was obtained in the same manner as in Example 45, with the exception that 5-fluoro-4-methyl-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11 NMR (500MHz, Me0D): 6 9.50(s. 114), 7.69(dd, 1H). 7.46(t. Ii-I'), 4.76(m, 2H), 3.61(m, 1H), 3.00(m, 211), 2.77(s, 3H), 2.25(m, 211), 2.13(m. 2H), 2.02(m, IF!), 1.79(m, 2H), 1.57(m, 1H) Example 66: Preparation of (2R,IS)-2-(3-(4-chloro-5-(trifluoromethyl)-1H-benzoldJimidazol-1-Apropyl)piperidin-3-ol dihydrochloride õOH 11:7-N CI

HCI HCI
The title compound (27 mg, yield: 95%) was obtained in the same manner as in Example 45, with the exception that 4-chloro-5-(trifluoromethy1)-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45, NMR (500MHz, Me0D): 6 9.65(s, 1H), 8.13(d, 1H), 8.01(d, 111), 4.64(m, 2H), 3.61(m, 2H), 2.98(m, 2H), 2.26(m, 2H), 2.10(m, 2H), 1.98(m, 1H), 1.76(m, 2H), I .56(m, 1H) Example 67: Preparation of (2R,3S)-2-(3-(7-chloro-6-(trifluoromethyl)-1H-benzoldjimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride õOH
HCI HCI
Cl The title compound (23 mg, yield: 91%) was obtained in the same manner as in Example 45, with the exception that 4-ch1oro-5-(trifluoromethyl)-1H-benzo[d]imidazole was used instead of 5-brorno-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11-1 NMR (500MHz, Me0D): 6 9.59(s, 114), 8.01(d, I ET), 7.96(d, 11-1), 4.91(m, 21-1), 3.61(m, 1H), 2.98(m, 21-1), 2.270, 2H), 2.10(m, 2H), 2.01(m, I H), 1.80(m, 2H), 1.56(m, 1H) Example 68: methyl 7-bromo-1-(3-02R,3S)-3-hydroxypiperidin-2-yppropy1)-1H-benzo[d]inuidazole-5-carboxylate dihydrochloride ,OH
=
r;:-N
HCI HCI
Br 0-The title compound (22 mg, yield: 89%) was obtained in the same manner as in Example 1, with the exception that methyl 3-bromo-4-tluoro-5-nitrobenzoate was used instead of 4-thloro-2-fluoro-l-nitobenzene in Step 1-8 of Example I.
1H NMR (500MHz, Me0D): 6 8.85(s, 1Ff),8.38(s, 1H), 8.27(s, 1H), 4.750n, 2H).
3.96(s.
3H), 3.57(m, 1H), 2.98(n. 2H), 2.25-1.98(m, 51-1), 1.72011, 2H), 1.54(m, 1H) Example 69: Preparation of (2R,3S)-2-(3-(7-bromo-5-chloro-11-1-benzoldjimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride PH
N
CI
HCI HCI
Br The title compound (24 mg, yield: 90%) was obtained in the same manner as in Example I, with the exception that 1-bromo-5-chloro-2-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
NMR (500M1-lz, Me0D): 6 9.28(s, 1H), 7.87(m, 21-1), 4.77(m, 2E1), 3.59(m, 114), 2.93(m, 2H), 2.18(m, 2I-f), 2.08(m, 2H), 2.02(m, 1H), I .75(m, 2H), 1.55(m, 1H) Example 70: Preparation of (2R,3S)-2-(3-(5-bromo-7-chloro-1H-benzo[dlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride Br HCI HCI
CI
The title compound (23 mg, yield: 89%) was obtained in the same manner as in Example 1, with the exception that 5-bromo- 1 -chloro-2-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example 1.
11 NMR (500MHz, Me0D): 6 9.35(s, 11-1), 8.00(s, II-f), 7.84(s, II-1), 4.78(m, 2I-f), 3.58(m, 1H), 2.97(m, 2H), 2.21(m, 2H), 2.08(m, 2H), 1.99(m, 1H), 1.74(m, 2H), 1.53(m, 1H) Example 71: Preparation of (2R,3S)-2-(3-(7-bromo-5-(trifluoromethyl)-1H-benzoidjimidazol-1-yppropyl)piperidin-3-ol dillydrochloride Br The title compound (19 mg,- yield: 89%) was obtained in the same manner as in Example 1, with the exception that 1-bromo-2-fluoro-3-nitro-5-(trifluoromethypbenzene was used instead of 4-chloro-2-fluoro-1-nitobenzene in Step 1-8 of Example 1.
NMR (500MHz, Me0D): 6 9.26(s, 1H), 8.11(s, 11-1), 8.02(s, 1H), 3.550m, I H), 2.90(m, 2H), 2.180m, 2H), 2.050m, 2H), 1.94(m, 1H), 1.71(m, 2H), 1.520m, I H) Example 72: Preparation of (2R,3S)-2-(3-(6713romo-4-fluoro-lH-benzoidlimidazol-1-Apropyl)piperidin-3-ol dihydroehloride ,OH
F
HCI HCI
Br The title compound (23 mg, yield: 90%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-4-fluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl- I H-benzo[d]imidazole in Step 45-1 of Example 45.
'H NMR (500MHz. Me0D): 6 9.44(s, 1H), 8.I2(s, 1H), 7.65(d, 1H), 4.55(m. 2H), 3.65(m, 1H), 3.57(m, 1H), 2.980-n, 214), 2.260n, 211), 2,100, 2H), 1.98(m, 1H), 1.74(m, 2H), I .54(m, 1H) Example 73: Preparation of (2R,3S)-2-(3-(5-bromo-7-11uoro-111-benzoidlirnidazol-1-y0propyl)piperidin-3-ol dihydrochloride OH
,-N
Br HCIHC
The title compound (24 mg, yield: 92%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-4-fluoro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11-1 NMR (500MI Me0D): 6 9.55(s, 11-1), 7.92(s, 1H), 7.69(d, 1H), 4.65(m, 2H), 3.61(m, 1H), 2.96(m, 2E1), 2.15(m, 2H), 2.07(m, 2H), 1.980m, 1H), 1.75(m, 2H), 1.53(m, 1H) Example 74: Preparation of (2R,3S)-2-(3-(7-chloro-4-fluoro-1H-benzo[dJimidazol-2 5 1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
HCI HCI
CI
The title compound (9 mg, yield: 45%) was obtained in the same manner as in Example 45, with the exception that 7-chloro-4-tluoro-1H-berizo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11-1 NMR (500MHz, Me0D): 6 9.43(s, 1H), 7.60(dd, 11-1), 7.38(t, IF-f), 4.82(m, 21-1), 3.54(m, 1H), 2.98(m, 2H), 2.24(m, 2H), 2.16(m, 21-1), 1.99(m, 1H), I .72(m, 2H), I .55(m, 1H) Example 75: Preparation of (2R,3S)-2-(3-(5-bromo-4-nitro-1H-benzold I imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride r-N NO2 HCI
H HCI Br The title compound (23 mg, yield: 90%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-4-nitro-1H-benzo[dlimidazole was used instead of 5-brorno-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11-1 NMR (500MHz, Me0D): 6 8.81(s, 1H), 7.95(d, 11-), 7.82(d, 1H), 4.51(m.
2H), 3.53(m, 1H), 2.92(m, 21-1), 2.10(m, 21-1), 2.04(m, 31-1), 1.68(m, 21-1), 1.57(m, 1H) Example 76: Preparation of (2R,3S)-2-(3-(6-bromo-7-nitro-1 H-benzofdlimidazol-i-yl)propyl)piperidin-3-ol dihydrochloride H HCI HCI

Br The title compound (18 mg, yield: 87%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-4-nitro-1H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
i1-1 NMR (500MHz, Me0D): 6 8.51(s, 111), 7.84(d, 111), 7.68(d, IH, 4.24(t. IF-f).
3.52(m, 1H), 2.97(m, 2H), 2.00(m, 5H), 1.73(m, 1H), 1.63(m, I H), 1.53(m, 1H) Example 77: Preparation of (212,3S)-2-(3-(4-chloro-5-nitro-1H-benzordlimidazol-yppropyl)piperidin-3-ol dihydrochloride CI

HCI HCI
The title compound (23 mg, yield: 92%) was obtained in the same manner as in Example 45, with the exception that 4-chloro-5-nitro- I H-benzo[d]imidazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
NMR (500MHz, Me0D): 6 8.76(s, 1H), 8.06(d, 1H.), 7.86(d. 1H), 4.51 (m, 2H), 3.66(m, I H), 2.98(m, 2H), 2.08(m, 2H), 1.99(m 3H), 1.74(m, 3H), 1.56(m, 11-1) Example 78: Preparation of (2R,3S)-2-0-(7-chloro-5-(trifluoromethyl)-114-benzo[d]imidazol-1-y1)propyppiperidin-3-ol dihydrochloride õOH
N N

CI
The title compound (19 mg, yield: 87%) was obtained in the same manner as in Example .. 1, with the exception that 1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example 1.
I NMR (500M1-lz, Me0D): 6 9.32(m, 1H), 8.07(d, 111), 7.83(d, 1H), 4.78(s, 1H), 3.58(m, 1H), 3.44(m, 11-1), 3.00(m, 1H), 2.93(m, 2H), 2.20-2.05(m, 4H), 2.02(m, I H), 1.97(m, 2H), 1.52(m, 1H) Example 79: Preparation of (2R,3S)-2-(3-(5-ch1oro-7-fluoro-1H-benzo[dlimidazol-1-y1)propyppiperidin-3-ol dihydrochloride õOH
H HCI CI
HCI F
The title compound (22 mg, yield: 88%) was obtained in the same manner as in Example 2 5 1, with the exception that 5-chloro- I ,2-difluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-l-nitobenzene in Step 1-8 of Example I.
1E1 NMR (500MHz, MeOD): 6 9.39(m, 11-1), 7.71(in, 1H), 7.49(m, I H), 4.59(m, 21-1), 3.57(m, 1H), 3.44(m, 1H), 3.29(m, 114), 2.97(in, 2H), 2.18(m, 2H), 2.07(m, 1H), 1.72(m, 2H), 1.51(m, 1H) Example 80: Preparation of (21;c3S)-2-(3-(5,7-dichloro-1H-benzold I imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride N
HCI HCI CI
CI
The title compound (7 mg, yield: 31')/0) was obtained in the same manner as in Example 1, with the exception that 1,5-dichloro-2-fluoro-3-nitrobenzene was used instead of 4-chloro-2-fluoro-1-nitobcnzene in Step 1-8 of Example I.
11-1 NMR (500MHz, Me0D): 6 9.30(s, I H), 7.84(s, 11-1). 7.69(s, I FI), 4.78(m, 211), 3.69(m, IF-I), 3.30(m, 1H), 2.99(m, 2H), 2.25(m, 2H), 2.16(m, 2H), 2.06(m, 1H), 1.78(m, 21-1), 1.51(m, 1H) Example 81: Preparation of (2 R,3S)-2-(3-(5-chloro-7-( I H-pyrazol-4-y1)-11-1-benzoidlimidazol-l-yl)propyl)piperidin-3-ol dihydrochloride ,OH
HCI HC CII
HN, The title compound (8 mg, yield: 14%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (IH-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 6 9.37(s, 110, 7.97(s, 21-1), 7.88(s, IN). 7.49(s, IN), 4.28(m, 2H), 3.44(m, IN), 2.91(m, 1H), 2.75(m, I H), 1.960m, 2H), 1.74-1.62(m, 3H), 1.50(m, 1H), 1.36(m, 1H) Example 82: Preparation of (2R,.3S)-2-(3-(7-(1H-pyrazol-4-y1)-5-(trifluoromethyl)-1 H-benzo( dlintidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,OH
N

HN, The title compound (9 mg, yield: 15%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3 -(4-bromo- I F{-benzo[d]irnidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate in Step 20-2 of Example 20.
'Fl NMR (500MHz, Me0D): 6 9.06(m, 1H), 8.10(s, 11-1), 7.97(s, 2H), 7.61(s, 111), 4.26(m, 2H), 3.44(m, 1H), 3.17(m, 1H), 2.93(m, 1H), 2.76(m, 1H), 1.99(m, 2H), 1.67(m, 3H), 1.53(m, 1H), 1.49(m, 1H) Example 83: Preparation of (2R,3S)-2-(3-(5-chloro-7-(3-fluoropheny1)-1H-benzo[dlimidazol-1-yl)propyppiperidin-3-ol dihydrochloride ,OH
N
H HCI HCI CI
The title compound (13 mg, yield: 22%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]im idazol-1-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine- I -carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yl)propyl )-3 -((tert-butyldimethylsi lypoxy)pipen di ne-l-carboxylate in Step 20-2 of Example 20.

NMR (500MHz, Me0D): 6 9.39(s, I H). 7.95(d, 1H), 7.64(m, 1H), 7.62(m, I H), 7.39(m, 2H), 7.34(m, 1H), 4.15(m, I H), 4.05(m, 2H), 3.41(m, 1H), 3.18(m, 11-1), 2.91(t, 1H), 2.87(s, 1H), 2.01(m, 2H), I .96(m, 2H), 1.50(m, 2H), 1.33(m, I H) Example 84: Preparation of (2R,3S)-2-(3-(7-(3-fluorophenyI)-5-(trifluoromethyl)-1H-benzo[djimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride The title compound (11 mg, yield: 20%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d]imidazol-1-y0propyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.62(s, IF-I), 8.24(m, 2H), 7.74(m. 11-1), 7.64(m, 114), 7.42(m, 31-1), 4.15(m, 2H), 3.43(m, I H), 3.21(m, 11-1), 2.91(m, 1H), 2.74(m, 1H), 1.97(m, 21-1), 1.73(m, 31-I), I .52(m, 2H), 1.33(m, 1H) Example 85: Preparation of (2R,3S)-2-(3-(5-chloro-7-(2-methylthiazol-5-y1)-1H-benzokilimidazol-1-yppropyl)piperidin-3-ol ,OH
_N
H HCI HCI CI
N s The title compound (6 mg, yield: 12%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d] im idazo I-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate, and that (2-inethylthiazol-5-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.68(s, 1H). 8.06(m, 21-1), 7.71(s, I H), 4.30(t, 2H), 3.52(m, I H), 3.27(m, 11-f), 2.95(m, 1H), 2.84(s, 314), 2.83(s, 1H), 2.05-1.89(m, 4H), 1.88(m, 2E1), 1.74(m, 2H) Example 86: Preparation of (2R,35)-2-(3-(5-chloro-7-(pyridin-3-yl)-11-1-benzokilimidazol-1-yl)propyl)piperidin-3-ol trihydrochloride N
N
3 HC)/ CI
\ /
The title compound (8 mg, yield: 15%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that pyridin-3-ylboronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.55(s, I H), 9.16(s, 11-1), 9.03(s, 111), 8.74(s, 1H). 8.18(s, IF!), 8.09(s, IH), 7.68(s, I H), 4.10(m, 21-1), 3.46(m, I H), 3.24(m, 11-1), 2.92(m, I H), 2.78(m, I H), 2.03(m, 11-1), 1.98(m, 1H), I.95-1.93(m, 3H), 1.52(m, 1H), 1.44(m 2H) Example 87: Preparation of (2R,3S)-2-(3-(5-chloro-7-(5-fluoropyridin-3-yl)-1H-benzo[dlimidazol-1-yppropyl)piperidin-3-ol trihydrochloride /
The title compound (9 mg, yield: 16%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro- I H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yppropy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (5-fluoropyridin-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.70(s, 11-1), 8.86-8.75(m, 2H), 8.I9(m, IH), 8.07(s, IH), 7.67(s, 1H), 4.11(m, 21-1), 3.47(m, 11-0, 3.24(m, 1H), 2.93(td, 1H), 2.77(s, 11-1), 2.01-2.00 (m, 2H), 1.93- I .82(m, 3H), 1.73(s, I H), I .65(m, 1H) Example 88: 5-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-benzoldlimidazol-7-y1)-1-methylpyridin-2(IH)-one dihydrochloride N
/
HCI CI
HCI
N

The title compound (10 mg, yield: 16%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,38)-2-(3-(4-bromo-IF1-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate, and that (1-methy1-6-oxo-1,6-dihydropyridin-3-yOboronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500M_Hz, Me0D): 6 9.55(m, 1H), 7.98(d, 2H), 7.74(d, 11{), 7.57(s, 111), 6.71(d, 1H), 4.32(m, 2H), 3.67(s, 31-I), 3.44(s, 1H), 3.24(m, 1H), 2.88(t, Iff), 2.80(s, 1H), 2.03-1.89(m, 4H), 1.71(m, 2H), 1.49(m, 2H) Example 89: Preparation of (2R,3S)-2-(3-(5-chloro-7-(1-(difluoromethyl)-1H-pyrazol-4-y1)-11-1-benzokflimidazol-1-y0propyl)piperidin-3-ol dihydrochloride H CI
HCI CI
F
The title compound (9 mg, yield: 14%) was obtained in the same manner as in Example 20, with the exception that tcrt-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzokflimidazol- I -yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (1-(difluoromethyl)-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz. Me0D): (3 9.46(s, 1H), 8.50(s, 1H). 8.05(s, 1H), 7.94(s. H).
7.56(s, 1H), 4.28(m, 2H), 3.49(m, 1H). 3.24(m, I H), 2.94(t, I H), 2.89(m, 1H), 2.01(m, 2H), 1.80(m, 2H), 1.72(m, 2H), 1.64(m, I H), I .55(m, I H) Example 90: Preparation of (2R,3S)-2-(3-(5-chloro-7-(isoxazol-3-yl)-111-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride N
rr;
HCI HCI CI
The title compound (7 mg, yield: 12%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that isoxazol-3-ylboronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 9.53(s, 1H), 8.04(m, 2H), 7.92(s, 1K), 7.69(m, 1H), 4.61(m, 2H), 3.61(m, 1H), 3.02(m, 2H), 2.28(m, 2H), 2.04(m, 2H), I.99(m, H), I.78(m, 2H), I .52(rn, 1H) Example 91: Preparation of (212,3S)-2-(3-(5-ch1oro-7-(thiophen-3-y1)-1H-benzoldlimidazol-1-yppropyl)piperidin-3-ol dihydrochloride N
HCI HCI CI
/
The title compound (24 mg, yield: 31%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-11-1-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)pipetidine- 1 -carboxylate, and that thiophen-3-ylboronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz, Nle0D): 6 9.52 (s 1H). 7.93(s, 1H), 7.73(d, 2H), 7.52(s, 1H).
7.36(d, 1H), 4.22(m, 2H), 3.48(m, 1H), 3.23(m, 1H), 2.93(t, 11-1), 2.76(m, 1E-1), 2.02(m, 2H), 1.78-1.63(tn, 3H), 1 .62(m, 1H), 1.57(m, 1H), 1.55(m, 1H) Example 92: Preparation of (2R33S)-2-(3-(5-chloro-7-(2-rnethylthiophen-3-y1)-benzokilimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride ,s0H N
CI
HCI HCI

The title compound (20 mg, yield: 25%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-ch1oro-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (2-methylthiophen-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
IH NIVIR (500MHz, Me0D): 6 9.56(s, 1H), 7.95(s, 1H), 7.47(d, 2H), 7.15(d, 1H), 4.22(in, 1H), 4.15(m, 1H), 3.50(m, 1H), 3.25(m, Iff), 2.91(t, 1H), 2.8! (in.
11-1), 2.34(d, 31-1), 2.01(m, 2H), 1.99-1.96(m, 3H), 1.79(m, I H), 1.65(m, 11-1), 1.56(m, 1H) Example 93: Preparation of (2R,3S)-2-(3-(5-chloro-7-(3,5-dimethylisoxazol-4-yl)-1H-benzo[dlimidazol-1-yppropyl)piperidin-3-ol dihydrochloride OH N

Cl HCI
N/
The title compound (19 mg, yield: 24%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)pipetidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d] imidazol-1 -yl)propyl)-3 -((tert-1 0 butyldimethylsilyl)oxy)piperidine-1-carboxylate, and that (3,5-dimethylisoxazol-4-yl)boronic acid was used instead of (3-tluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.58(s, IF!), 8.04(s. 1H), 7.71(s, 1H), 4.23(m, 2H).
3.61(rn, 1H), 3.01(m, 1H), 2.97(m. 1H), 2.39(s, 3H), 2.18(s, 3H), 2.17-2.11(m, 3H), 2.04(m, 2H), 1.86(m, 214), I.71(m, 2H) Example 94: Preparation of (2R,3S)-2-(3-(5-chloro-7-(3,6-dihydro-2H-pyran-4-yI)-I H-benzofdjimidazol-l-Apropyppiperidin-3-ol dihydrochloride =' H
HCI CI
The title compound (22 mg, yield: 27%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-brorno-5-chloro-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-berrzo[4]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (3,6-dihydro-214-pymn-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.

NMR (500MHz, Me0D): 6 9.60(s, 110 7.85(s, 111), 7.51(s, 1H), 6.08(s, 1H), 4.60(t, 2H), 4.39(s, 2H), 4.03(t, 2H), 3.61(m, IH), 2.99(in,2H), 2.58(s, 2H), 2.12-1.96(m, 5H), 1.72(m, 2H), 1.51(m, 1H) Example 95: Preparation of (212,35)-2-(3-(7-(1-((1,3-dioxolan-2-yl)methyl)-1H-pyrazol-4-y1)-5-chloro-1H-benzold I ropyl)piperidin-3-ol dihydrochloride µ(:)F1 HCIr:N
CI
HCI
\
/0y \--0 The title compound (17 mg, yield: 22%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro- I H-benzo[d]im idazol-1-1 0 yl)propy1)-3-((tert-butyldimethylsily0oxy)piperidine-l-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3 -(4-bromo-1H-benzo[d]im dazol- I -y0propyl)-3 -((tert-butyldim ethyl silyl )oxy)pi peridi ne-1 -carboxylate, and that (1-(( 1,3-d ioxol an-2-y1 )111 ethyl )-1H-pyrazol-4-yl)boronic acid was used instead of (3-tluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.62(s, 1H), 8.07(s, 1E0, 7.93(s, 11-0, 7.82(s, I
El), 7.53(s, 11-1), 4.43(m, 2H), 4.41(m, 2H), 3.97(m, 2H), 3.56(m, 11-0, 3.25(m, I H), 2.96(t, 1H), 2.96(s, 1H), 2.01(m, 1H), 1.82-1.65(m, 5H), 1.56(m, I H), 1.51(m. 1 Fl) Example 96: Preparation of (2R,3S)-2-(3-(5-chloro-7-(1-methyl-1H-imidazol-5-y1)-2 0 1 H-benzold imidazol-1-yl)propyl)piperidin-3-ol triihydrochloride õOH

N N
The title compound (20 mg. yield: 29%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzokilimidazol- (-7,1 yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (1-methyl-1H-imidazol-5-y1)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500M1-1z. Me0D): 6 9.20(s, 1H), 9.12(d, IR), 8.01(s, 1H), 8.00(s, 1H), 7.68(s, IFf), 4.20(s, 1H), 3.94(s, 1H), 3.78(s, 3H), 3.47(m, 1H), 2.94(t, 1H), 2.89(m, 1H), 2.06(m, 1H), 1.97(m, 1H), 1.85(m, 2H), 1.83-1.74(m, 3H), 1.53(m, 2H) Example 97: Preparation of (2R3S)-2-(3-(5-ehloro-7-(1-methy1-1H-pyrazol-4-y1)-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride ,µQHHCI _N
H HCI CI
¨N, The title compound (15 mg, yield: 25%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)bororlic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.30(s, 11-0, 7.97(s, 1H), 7.87(s, 1H), 7.76(s. 1H), 7.45(s, 1H), 4.32(m, 2H), 4.02(s, 3H), 3.24(m, 1H), 2.92(m, 1H), 2.77(m, 1H), 2.00(m, 2H), I.71(m, 4H), 1.51(m, 1H), 1.40(m, 1H) Example 98: Preparation of (2R,3S)-2-(3-(7-(pyrrolidin-1-y1)-11R-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride /
HCI
cN) The title compound (12 mg, yield: 20%) was obtained in the same manner as in Example 18, with the exception that tert-butyl (2R,3S)-2-(3-(7-brorno-1H-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilypoxy)piperidine- I -carboxylate in Step 18-2 of Example 18.
IF1 NMR (500MHz, Me0D): 6 9.44(s, 1H), 7.55(m, 3H), 4.76(t, 21-1), 3.56(m, Ii-I), 3.20(m, 414), 2.94(m, 2H), 2.20(m, 2H), 2.07(m, 5H), 2.00(m, 3H), 1.74(m, 2H), 1.53(in, 11-1) Example 99: Preparation of (2R93S)-2-(3-(5-eliloro-7-(pyrrolidin-l-y1)-1H-benzo[djimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride ,OH HCI
H HCI CI
The title compound (13 mg, yield: 21%) was obtained in the same manner as in Example 18, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-y0propyl)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl . (2R,3S)-2-(3-(4-brorno-IH-benzo[d]imidazol- I -yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate in Step 18=2 of Example 18.
NMR (500MHz, Me0D): 6 9.46(s, 1H), 7.58(d, 1H). 7.47(d, 1H), 4.72(m, 214), 3.53(m, 1H), 3.21(m, 4H), 2.94(m, 2H), 2.20(m, 2H), 2.11(m, 5H), 1.96(m, 2H), 1.77(m, I H), 1.63(m, 1H), I .52(m, 1H) Example 100: Preparation of (2R93S)-2-(3-(5-chloro-7-(2-eyelopropyltItiazol-5-31)-1H-benzofdlimidazol-1-y1)propyppiperidin-3-ol dihydrochloride OH HCI
H HCI CI
N s The title compound (12 mg, yield: 25%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine- 1 -carboxyl ate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1 Fl-benzo[d] im idazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-l-carboxylate, and that (2-cyclopropylthiazol-5-yl)boronic acid was used instead of (3-tluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.51(s, 1H), 7.97(s, 1H), 7.73(s, 1H), 7.70(s, 1H), 4.63(m, 2H), 3.42(m, 1H), 3.22(m, 1H), 2.93(m, 1H), 2.77(m, 1H), 2.50(m, 1H), 1.95(m, 2H), 1.68(m, 41-1), 1.50(m, 21-1), 1.23(m, 21-1), 1.11(m, 21-1) Example 101: Preparation of (2R,3S)-2-(3-(5-chloro-7-(1-(thiazol-2-y1)-1H-pyrazol-4-y1)-1H-benzoldlimidazol-1-yl)propyl)pipericlin-3-ol dihydrochloride HCI HCI CI
N/
N
The title compound (17 mg, yield: 30%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol- -yl)propy1)-3-((tert-butyldimethy1silypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-11-1-benzo[dJimidazol-1-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (1-(thiazol-2-y1)-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.41(s, 1H), 8.83(s, 1H), 8.10(s, 11-1), 7.95(s, 114), 7.65(s, 1H), 7.61(s, 1H), 7.47(s, 1H), 4.37(m, 214), 3.44(m, 1H), 3.18(m, 1H), 2.87(m, 1H), 2.78(m, 11-{), 1.92(m, 21-1), 1.82(m, 2H), 1.65(m, 21-1), 1.43(ni, 21-1) Example 102: Preparation of (2R,3S)-2-(3-(5-chloro-7-(1-(oxetan-3-y0-114-pyrazol-2 5 4-y1)-1H-benzo[d I imidazol-1-yl)propyl)piperidin-3-ol dihydrochloride HHCI
HCI CI
N/

The title compound (12 mg, yield: 23%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3-(4-bromo-1H-benzo[d] im idazol-1-yl)propy1)-3-((tert-butyldi methyl si lyl)oxy)pipendine-l-carboxylate, and that (1-(oxetan-3-y1)-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.58(s, I H), 8.15(s, 1H), 7.92(s, 1H), 7.87(s, 1H).
7.54(s, 1H), 4.68(m, !H), 4.34{m, 2H), 4.03(m, 214), 3.50(m, 1H), 3.22(m, 1H), 2.92(m, 1H), 2.85(m, 1H), 1.95(m, 2H), 1.78(m, 4H), 1.64(m, 1H), 1.42(m, 1H) Example 103: Preparation of (2R,3S)-2-(3-(5-chloro-7-(2-(tetrahydro-211-pyran-yl)thiazol-4-y1)-1H-benzo[d I imidazol-1-yl)propyl)piperidin-3-ol dihydrochlotide N
CI
HCI
S N

The title compound (10 mg, yield: 18%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-ehloro-IH-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsi1y1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (2-(tetrahydro-2H-pyran-4-yl)thiazol-5-2 0 yl)boronic acid was used instead of (3-tluorophenyl)boronic acid in Step 20-2 of Example 20.
I\IMR (500MF1z, Me0D): 6 9.63(s, 110, 7.98(s, I H), 7.73(S, 1Ff), 7.21(s, 1H), 4.65(m, 2H), 3.84(m, 411), 3.62(m, 4H), 3.48(m, 1H), 3.25(m, 1H), 2.94(m, 11-[), 2.81(m, 1H), 1.99(m, 3H), 1.82(m, 4H), 1.54(m, 21-f) Example 104: Preparation of (2R,3S)-2-(3-(5-chloro-7-(furan-3-y1)-1 H-benzo(dlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride OH HC!
CI' HCI
r, The title compound (9 mg, yield: 15%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3-(4-bromo-1H-benzo[d]im idazol-1-yl)propy1)-3 -((tert-butyldimethylsilyl)oxy)piperidine- I -carboxylate, and that furan-3-ylboronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
'1-1 NMR (500MHz, Me0D): 6 9.55(s, 11-1). 8.05(d, I H), 7.93(s, 1H), 7.69(d.
11-1), 7.50(m, 1H), 7.32(m, 1H), 4.63(m, 2H), 3.61(m, 1H), 3.02(m, 1H), 2.94(m, 1H), 2.26(m, 2H), .. 2.09(m, 2H), 2.01(m, I H), 1.78(m, 2H), 1.53(m, 11-1) Example 105: 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-111-benzoidjimidazol-7-yl)thiazole-2-carbonitri1e dihydrochloride r--CI
HCI
N
NC
The title compound (14 mg, yield: 20%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro- I H-benzokiJimidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I 1-1-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-l-carboxylate, and that (2-cyanothiazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.54(s, 1H), 8.29(s, I 1 1), 8.02(s, 11-1), 7.79(s, 111), 4.57(m, 2H), 3.42(m, 1H), 3.20(m, 11-1), 2.91(m, 1H), 2.76(m, 1H), 1,95(m.
2H), 1.60(m, 4H), 1.52(m, 1H), 1.41(m, 1H) Example 106: Preparation of (2R,3S)-2-(3-(7-(1-(tert-buty1)-1H-pyrazol-4-y1)-5-chloro-lH-benzoldlimidazol-1-yppropyppiperidin-3-ol dihydrochloride HCI
N
HCI CI
The title compound (10 mg, yield: 18%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-114-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-yppropy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate, and that (1 -(tert-butyl)- I
H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz, Me0D): 6 9.52(s, 1H), 8.14(s, 111), 7.89(s, 1H), 7.80(s, 111), 7.51(s, 1H), 4.36(m, 2H), 3.48(m, 1H), 3.23(m, I H), 2.95(in, H), 2.82(m, 1K), 2.01(m, 2H), 1.8 (m, 2H), 1.73(m, 11H), 1.53(m, I H), 1.43(m, 1H) Example 107: Preparation of (2R,3S)-2-(3-(5-chloro-7-(1-isopenty1-1H-pyrazol-4-2 0 y1)-1H-benzo[diimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride H HCI CI
N
The title compound (17 mg, yield: 25%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxyl ate was used instead of teit-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol- I -yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (I-isopentyl- I H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
IHNMR (500MHz, Me0D): 6 9.47(s, 11-1), 8.04(s, 1H), 7.89(s, 1H), 7.78(s, 1H), 7.50(s, 11-1), 4.320m, 4H), 3.45(m, 1H), 3.23(m, I H), 2.95(m, 1H), 2.780m, 1H), 2.00(m, 2H), 1.87(m, 2H), 1.76(m, 2H), 1 .64(m, 4H), 1.54(m, 1H), 1.42(m, 1H), 1.02(s, 6H) Example 108: Preparation of (2R,38)-2-(345-chloro-7-(1-isopropyl-1H-pyrazol-4-y1)-1H-benzo[dlimidazol-1-Apropyl)piperidin-3-ol dihydrochloride HCI
,,OH
CI
HCI
The title compound (15 mg, yield: 21%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3 S)-2-(3 -(7-bromo-5-chloro- I H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3 -(4-brorno-1H-benzo[d] im idazol-1-yppropy1)-3-((tert-butyldimethylsi lyl )oxy)piperidine-l-carboxylate, and that (1 -isopropy1-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.48(s, 1H), 8.07(s, 1H), 7.90(s, 11-I), 7.79(s, 11-1), 7.52(s, 1H), 4.700m, I H), 4.30(m, 2H), 3.45(m, 1H), 3.24(m, 1H), 2.93(m, 1H), 2.80(m, 1H), 1.99(m, 2H), 1.71(n, 2H), [670m, 2H), 1.59(s, 6H), 1.53(m, I H), 1.40(m, 1H) Example 109: Preparation of (2R,38)-2-(3-(5-chloro-7-(4-methylthiophen-3-yl)-benzoldlimidazol-1-y1)propyl)piperidin-3--ol dihydrochloride HCI
CI
HCI

The title compound (20 mg, yield: 31%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- I H-benzo[d]irnidazol-1-y1)propy1)-3-((tett-butyldimethylsilyl)oxy)piperidine- 1 -carboxylate, and that (4-methylthiophen-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
IHNMR (500MHz, Me0D): 6 9.53(s, 1H), 7.95(s, I H), 7.63(s, 11-1), 7.48(s, 1H), 7.34(s, 1H), 4.23(m, I H), 3.96(m, I H), 3.51(m, 1H), 3.23(m, 11-1), 2.96(m, 11-1), 2.81(m, 1H), 2.06(d, 3H), 1.99(m, 2H), 1.76(m, 3H), 1.57(m, 2H), 1.42(m, 1H) Example 110: ethyl 3-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-benzoldlimidazol-7-y0furan-2-carboxylate dihydrochloride HCI
CI
HC I

The title compound (10 mg, yield: 21%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-brorno-5-chloro-1H-benzo[d]imidazol- -yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine- 1 -carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-11-1-benzo[dlimidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (2-(ethoxycarbonyl)furan-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
NMR (500MHz. Me0D): 6 9.53(s, 1H), 8.00(s, I H), 7.97(s, 11-f), 7.55(s, 1H), 6.96(s, 1H), 4.29(m, 1H), 4.15(m, 3H), 3.47(m, 1H), 3.24(m, 2H), 2.94(m, 1H), 2.79(m, 1H), 1.97(m, 3H), 1.84(m, 2H), 1.72(m, 2H), 1.53(m, 2H), 1.08(t, 3H) Example 111: methyl 4-(5-chloro-1-(34(2R,3S)-3-hydroxypiperidin-2-yppropyl)-2 5 111-benzo[d]imidazol-7-y1)thiophene-2-carboxylate dihydrochloride õOH
HCIN
CI
HCI

The title compound (9 mg, yield: 19%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro- I H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine- I -carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol- I -yl)propyI)-3-((tert-butyldim ethylsi lyl)oxy)piperidine-l-carboxylate, and that (5-(methoxycarbonyl)thiophen-3 -yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NMR (500MHz, Me0D): 6 9.54(s, 1H), 8.05(d, 2H), 7.97(s, 1H). 7.57(s, 1H), 4.80(m, 11-0, 4.22(m, 2H), 3.93(s, 3H), 3.43(m, 1H), 3.22(m, 2H), 2.93(m, 1H), 2.78(m, 1H).
2.01(m, 2H), 1.78(m, 3H), 1.63(m, 1H), 1.53(m, 1H), 1.41(m, I H) Example 112: Preparation of (2R,3S)-2-(3-(5-ehloro-7-(1-(2-fluoroethyl)-111-pyrazol-4-y1)-1H-benzoldlimidazol-1-yppropyl)piperidin-3-ol dihydroehloride HCI
õOH N
CI
HCI
-N
Fj- =N
The title compound (15 mg, yield: 29%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-y1)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3 S)-2-(3-(4-bromo- I H-ben 70 [d] im idazol-l-yl)propy1)-3-((tert-butyldimethylsilyl )oxy)piperidine- I -carboxylate, and that (1-(2-fluoroethyl)- I Fl-pyrazol-4-2 0 yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
1H NMR (500MHz, Me0D): 6 9.53(s, I H), 8.09(s, 11-1), 7.91(s, I H), 7.85(s, 1H), 7.53(s, 111), 4.92(m, 1H), 4.64(m, I H), 4.56(m, I H), 4.32(m, 2H), 3.49(m, 1H), 3.23(m, I H), 2.94(m, 1H), 2.80(m, 1H), 1.96(m, 3H), 1.74(m, 4H), 1.54(m, 1H), 1.47(m, 1H) Example 113: Preparation of (2R,3S)-2-(3-(7-(1-butyl-1H-pyrazol-4-yl)-5-chloro-11-1-benzoidlimidazol-1-yl)propyppiperidin-3-ol dihydrochloride HCI
õOH N
N
CI
HCI
N
The title compound (18 mg, yield: 34%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propyl)-3-((tert-butyldimethylsilypoxy)piperidine- I -carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3-(4-bromo- 1 H-benzo[d]imidazol- 1 -yl)propyl)-3-((tert-butyldimethylsilypoxy)piperidine- 1 -carboxylate, and that (1-butyl- 1 H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
H NMR (500MHz, Me0D): 6 9.43(s, 111), 8.02(S, 1H), 7.89(s, 114), 7.79(s, 1H), 7.50(s, 1H), 4.30(m, 31-1), 3.45(m, 1H), 3.36(m, 1H), 3.22(m, 1H), 2.95(m, I H), 2.78(m, 1H), 2.01(m, 4H), 1.75(m, 4H), 1.54(m, 1H), 1 .42(m, 3H), 1.01(m, 3H) Example 114: Preparation of (2R,3S)-2-(3-(5-chloro-7-(2,5-dimethylthiophen-3-y1)-1H-benzoldlimidazol-1-Apropyl)piperidin-3-ol dihydrochloride HCI
CI
HCI
S
The title compound (12 mg, yield: 20%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1 H-benzo[d]imidazol-1-2 0 yl)propy1)-3-((tert-butyldimethylsily1)oxy)piperidine- 1 -carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo- 1 H-benzo[d]im idazol- 1 -yl)propy1)-3-((tert-butyldimethylsi lyl)oxy)piperidine- 1 -carboxylate, and that (2,5-dimethylthiophen-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
11-1 NM1Z (500MHz, Me0D): 6 9.54(m, 1H), 7.92(s, 1I-1), 7.44(s, 1H), 6.80(s, 11-1), 4.25(m, 1H), 4.09(m, 1H), 3.48(m, 1H), 3.25(m, 21-1), 2.95(m, 1H), 2.80(m, 1H), 2.51(s, 3H), 2.24(d,31-f), 1.99(m,31-1), 1.80(m, 2H), 1.66(m, 3H), 1.56(m, I H), 1.47(m, 1H) Example 115: Preparation of (2R,.3S)-2-(3-(5-chloro-7-(1-isobt1ty1-111-pyrazol-y1)-1 H-benzo Idlimidazol-1-yl)propyppiperidin-3-ol dihydrochloride HCI
/
CI
HCI
N
The title compound (18 mg, yield: 27%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propy1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2 R,3 S)-2-(3 -(4-bromo-11-1-benzo[d] im idazol-1-yppropy1)-3 -((tert-butyldimethylsilyl)ox y)piperidine-l-carboxylate, and that (1-isobuty1-1H-pyrazol-4-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
III NMR (500MI lz, Me0D): 6 9.53(s, 11-1), 8.03(s, 1H), 7.90(s, 1H), 7.80(s.
1H), 7.50(s, 1H), 4.33(m, 2H), 4.10(m, 2H), 3.48(m, 1H), 3.23(m, 11-1), 2.92(m, 1H), 2.81(m, 1H), 2.30(m, 11-1), 1.99(m, 2H), 1,81(m, 2H), 1.74(m, 2H), I .54(m, 1H), 1.44(m, 1H), 0.99(d, 6H) Example 116: ethyl 4-(5-chloro-1-(34(2F13S)-3-hydroxypiperidin-2-ybpropy1)-111-2 0 benzoidlimidazol-7-y1)-1-methyl-1H-pyrrole-2-carboxylate dihydrochloride =µ(31-1 HCIr_-N
N N
H HCI CI
N

The title compound (18 mg, yield: 31%) was obtained in the same manner as in Example 20, with the exception that tert-butyl (2R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yppropyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate was used instead of tert-butyl (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol-1-y1)propyl)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate, and that (5-(ethoxycarbony1)-1-methyl- 1H-pyrrol-3-yl)boronic acid was used instead of (3-fluorophenyl)boronic acid in Step 20-2 of Example 20.
I H NMR (500MHz, Me0D): 6 9.50(s, 114), 7.87(s, 1H), 7.49(s, 1 F), 7.31(s, IR), 7.15(s, 1H), 4.41(m, 2H), 4.32(m, 2H), 4.04(s, 3H), 3.42(m, 1H), 3.21(m, 1H), 2.92(m, 1H), 2.76(m, 1H), 1.96(m, 2H), 1.88-1.62(m, 51-1), 1.52(m, 2H), 1.40(m, 3H) Example 117: Preparation of (2R,38)-2-(3-(5-chloro-1H-imidazo[4,5-blpyridin-1-yl)propyl)piperidin-3-ol dihydrochloride _N
cI

The title compound (17 mg, yield: 35%) was obtained in the same manner as in Example 45, with the exception that 5-chloro- I H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methyl- I H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 9.48 (s, 114), 8.29 (d, 1H), 7.68 (d, 111), 4.58 (t, 2H), 3.66 (m, 2H), 3.00 (m, 211). 2.20 (m, 2H), 2.07 (in, 21-1), 1.98 (m, 1H), 1.74 (m, 21-1), 1.56 (m, 1H) Example 118: Preparation of (2R,3S)-2-(3-(5-chloro-3H-imidazo[4,5-lApyridin-3-y1)propyppiperidin-3-ol dihydrochloride N
N

CI
The title compound (15 mg, yield: 40%) was obtained in the same manner as in Example 45, with the exception that 5-chloro-3H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-2 5 methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 9.50 (s, IH), 8.46 (d, 1H), 7.69 (d, 1H), 4.59 (t, 3.65 (in, 1H), 3.58 (m, 1H), 2.99 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.97 (in, 1H), 1.73 (m, H), 1.54(m, 1H) Example 119: Preparation of (2R,3S)-2-(3-(5-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol dihydrochloride N
ps, Br The title compound (30 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-1H-irnidazo[4,5-b]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45, 1H-NMR (500 MHz, Me0D): 159.54 (s, 1H), 8.20 (d, 1H), 7.84 (d, 1H), 4.59 (t, 2H), 3.58 (m, 2E1), 2.99 (m, 2H), 2.24 (m, 2H), 2.07 (in, 2H), 1.98 (m, 1H). 1.74 (in, 2H), I .56 (in, 1H) Example 120: Preparation of (2R,3S)-2-(3-(6-bromo-1H-intidazo[4,5-bipyridin-l-yl)propyl)piperidin-3-ol dihydrochloride N
m /

Br The title compound (33 mg, yield: 82%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-1H-irnidazo[4,5-b]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): 6 9.50 (s, 1H), 8.78 (d, 114), 8.53 (d, 1H), 4.60 (t, 2H), 3.56(t, 1H), 2.98 (m, 2H), 2.26 (m, 2H), 2.21 (rn, 2H), 1.97 (m, 1H), 1.74 (m, 2H), 1.55(m, 1H) Example 121: Preparation of (2R,3S)-2-(3-(5-methyl-1H-imidazoK5-bI pyridin-1-yl)propyl)piperidin-3-ol dihydrochloride õOH N
/ IN

The title compound (19 mg, yield: 49%) was obtained in the same manner as in Example 45, with the exception that 5-methyl-1H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
'H-NMR (500 MHz, Me0D): 6 9.55 (s, 1H), 8.18 (d, 114), 7.58 (d, 1H), 4.63 (t, 214), 3.58 (m, 214), 3.00 (m, 2H), 2,74 (s, 3H), 2.24 (m, 2H), 2.06 (in, 2H), 1.98 (m, 1H), 1.74 (m, 2H), 1.56 (in, 2H), 1.56 (tn, 1H) Example 122: Preparation of (2R,3S)-2-(3-(6-chloro-1H-imidazo[4,5-cipyridin-1-yl)propyl)piperidin-3-ol dihydrochloride r--CI
The title compound (15 mg, yield: 40%) was obtained in the same manner as in Example 45, with the exception that 6-chloro-1H-imidazo[4,5-c]pyridine was used instead of 5-bromo-4-methy1-114-benzo[d]imidazole in step 45-1 of Example 45.
IH-NMR (500 MHz, Me0D): 6 9.30 (s, 1H), 9.09 (s, 114), 7.91 (s, 114), 4.62 (t, 214), 3.60 (m, 2H), 2.99 (m, 2H), 2.22 (m, 2H), 2.06 (in, 2H). 1.98 (in, 1H), 1.73 (m, 2H), 1.56 (m, 1H) Example 123: Preparation of (212,3S)-2-(3-(6-chloro-3H-imidazo14,5-clpyridin-3-y1)propyl)piperidin-3-ol dihydrochloride CI

The title compound (18 mg, yield: 37%) was obtained in the same manner as in Example 45, with the exception that 6-chloro-3H-imidazo[4,5-c]pyridine was used instead of 5-brorno-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
I H-NMR (500 MHz, Me0D): 6 9.21 (s, 1H), 8.97 (s, 1H), 8.18 (s, 1H), 4.52 (t, 214), 3.58 (m, 1H), 2.98 (m, 2H), 2.19 (in, 2H), 2.05 (m, 21-1), 1.97 (m, 1H), 1.73 (m, 2H), 1.56 (in, I H) Example 124: Preparation of (2R,3S)-2-(3-(6-bromo- 1-1-imidazo14,5-cjpyridin-1-yl)propyl)piperidin-3-ol dihydrochloride õOH
/

Br The title compound (18 mg, yield: 35%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-3H-imidazo[4,5-c]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 9.43 (s, 1H), 9.16 (s, 1H), 8.12 (s,.1H), 4.64 (t, 2H), 3.65 (m, 2H), 3.01 (in, 2H), 2.26 (m, 2H), 2.07 (m, 2H), 1.97 (m, 1H), 1.75 (m, 2H), 1.56 (m, I H) Example 125: Preparation of (2R,3S)-2-(3-(6-bromo-3H-imidazo[4,5-clpyridin-3-yl)propyl)piperidin-3-ol dihydrochloride The title compound (20 mg, yield: 40%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-3H-imidazo[4,5-c]pyridine was used instead of 5-bromo-4-methy1-1H-benzordjimidazole in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): 6 9.18 (s, 114), 9.01 (s, 1H). 8.38 (s, 1H), 4.53 (t.
2H). 3.58 (m, 21-1), 2.97 (in, 2H), 2.19 (m, 214), 2.05 (m, 2H), 1.97 (m, 1H), 1.74 (m, 2H), 1.56 (in, 11-1) Example 126: Preparation of (2R,3S)-2-(3-(7-chloro-111-imidazo[4,5-blpyridin-1-yl)propyl)piperidin-3-ol dihydrochloride õOH
N\

The title compound (25 mg, yield: 32%) was obtained in the same manner as in Example 45, with the exception that 7-chloro-1H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
Example 127: Preparation of (2R93S)-2-(3-(5,6-dichloro-11-1-imidazoI4,5-b1pyridin-=
1-yl)propyl)piperidin-3-ol dihydrochloride õOH
CI

The title compound (35 mg, yield: 48%) was obtained in the same manner as in Example 45, with the exception that 5,6-dichloro- I H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methyl- I H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 9.10 (s, 8.45 (s, 11-1), 4.50 (t, 2H), 3.56 (m, 1H), 2.98 (m, 2H), 2.21 (m, 2H), 2.03 (m, 3H), 1.69 (m, 2H), 1.53 (m, 1H) Example 128: Preparation of 1-dihydrochloride /

Br The title compound (18 mg, yield: 35%) was obtained in the same manner as in Example 45, with the exception that 7-bromo-1H-imidazo[4,5-c]pyridine was used instead of 5-bromo-4-methy1-11-1-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 9.66 (s, 1Ff), 9.07 (s, 11-1), 8.89 (s, 1H), 4.62 (t, 2H), 3.58 (m, 2H), 2.99 (m, 2H), 2.21 (m, 2H), 2.00 (m, 3H), 1.74 (m, 2H), 1.55 (m, 1H) Example 129: Preparation of (2R,3S)-2-(3-(5-(trifluoromethyl)-3H-imidazole4,5-131pyridin-3-y1)propyl)piperidin-3-ol dihydrochloride N
N

The title compound (20 mg, yield: 45%) was obtained in the same manner as in Example 45, with the exception that 5-(trifluoromethyl)-314-imidazo[4,5-10]pyridine was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
11-1-NMIZ (500 MHz, Me0D): 6 9.71 (s. 1H), 8.53 (d, 1H), 8.08 (d, 1H), 4.67 (t, 2H), 3.59 (m, 1H), 2.95 (m, 2H), 2.28 (m, 2H), 2.07 (m, 2H), 1.98 (m, 1H), 1.75 (m, 2H), 1.55 (m, 1H) Example 130: Preparation of (2R,3S)-2-(3-(6,7-dichloro-311-imidazo[4,5-b ipyridin-3-yl)propyl)piperidin-3-ol dihydrochloride õOH
r- CI
/
N ¨ CI

The title compound (25 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 6,7-dichloro-3H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methyl-1H-benzo[d]imida7ole in step 45-1 of Example 45.
11-1-NMR (500 MHz, Me0D): 6 8.62 (s, 1H), 8.51 (s, 11-1), 4.43 (m. 2H), 3.51 (m, 111), 3.22 (m, IH), 2.91 (m, 2H), 2.08 (m, 2H), 1.96 (m, 31i), 1.55 (m, 3H) Example 131: Preparation of (2[43S)-2-(3-(6-chloro-7-methy1-3H-irnidazol4,5-blpyridin-3-y1)propyl)piperidin-3-ol dihydrochloride OH
N/ ' The title compound (31 mg, yield: 84%) was obtained in the same manner as in Example 45, with the exception that 6-chloro-7-methyl-31-1-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): 6 9.68 (s, 1H), 8.67 (s, 1H), 4.62 (t, 2H), 3.57 (m, 2H), 2.97 (m, 2H), 2.74 (s, 3H), 2.25 (m, 2H), 2.06 (m, 2H), 1.97 (m, 1H), 1.75 (m, 2H), 1.53 (m, 1H) Example 132: Preparation of (2R,3S)-2-(3-(6-bromo-7-methy1-3H-imidazo[4,5-blpyridin-3-yl)propyl)piperidin-3-ol dihydrochloride õOH
/
N Br The title compound (35 mg, yield: 85%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine was used instead of 5-9!

bromo-4-methyl-1 El-benzo[d]imidazole in step 45-1 of Example 45.
'H-NMR (500 MHz, Me0D): 8 9.74 (s, 1H), 8.80 (d. II-I), 4.63 (t, 2H), 3.57 (m, 1H), 2.96 (m, 2H), 2.76 (s, 3H), 2.28 (m, 2H), 2.06 (m, 2H), 1.97 (m, 1H), 1.74 (m, 2H), 1.55 (m, 1H) Example 133: Preparation of (2R,3S)-2-(3-(6-bromo-7-chloro-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol dihydrochloride Br The title compound (30 mg, yield: 78%) was obtained in the same manner as in Example 45, with the exception that 6-bromo-7-chloro-3H-imidazo[4,5-b]pyridine was used instead of 5-.. bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
11-1-NMR (500 MHz. Me0D): 6 9.24 (s, 1H), 8.77 (s, 11-1), 4.55 (t, 21-1), 3.55 (m. 11-0, 3.26 (in, 1H), 2.97 (m, 2H), 2.23 (m, 2H), 2.03 (m, 3H), 1.70 (m, 2H), 1.54 (m, 1 14) Example 134: Preparation of (2R,3S)-2-(3-(7-chloro-6-(3-chloropheny1)-3H-1 5 imidazo[4,5-bJpyridin-3-yl)propyl)piperidin-3-ol dihydrochloride õOH
r=--N CI
CI
N

The title compound (28 mg, yield: 70%) was obtained in the same manner as in Example 45, with the exception that 7-chloro-6-(3-chloropheny1)-3H-imidazo[4,5-b]pyridine was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
I H-NMR (500 MHz, Me0D): 8 9.69 (s, 11-1), 8.67 (s, 114), 7.55 (m, 414), 4.66 (t, 21-1), 3.59 (m, 1H), 3.02 (m, 21-1), 2.33 (in, 2H), 2.07 (m, 21-1), 1.97 (m, 11-1), 1.56 (m, 2H), 1.55 (m, 1H) Example 135: Preparation of (21Z,3S)-2-(3-(2-chloro-7H-purin-7-y1)propyl)piperidin-3-ol trihydrochloride N

The title compound (15 mg, yield: 35%) was obtained in the same manner as in Example 45, with the exception that 2-chloro-7H-purine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
11-1-NMR (500 MHz, Me0D): 6 9.05 (s, 114), 8.81 (s, 1H), 4.44 (t, 2H), 3.55 (m, 11-1), 3.28 (m, 1H), 2.98 (m, 2H), 2.19 (m, 2H), 2.03 (m, 3H), 1.70 (m, 2H), 1.55 (m, 1H) Example 136: Preparation of (2R,3S)-2-(3-(2-chloro-9H-putin-9-.
yl)propyl)piperidin-3-ol trihydrochloride _N
f---CI
The title compound (12 mg, yield: 30%) was obtained in the same manner as in Example 45, with the exception that 2-chloro-9H-purine was used instead of 5-brorno-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
I H-NMR. (500 MHz. Me0D): 6 9.19 (s, 1H), 8.87 (s. 11-1). 4.52 (m, 21-1), 3.55 (m, 1H), 3.25 (m, 1H), 2.97 (m, 2H), 2.16 (in, 211), 2.00 (m, 31-1), 1.65 (in, 2H), 1.55 (m, 1H) Example 137: Preparation of (2R,3S)-2-(3-(6-(dimethylamino)-911-purin-9-yl)propyl)piperidin-3-ol trihydrochloride H N \
\ N
N

The title compound (25 mg, yield: 75%) was obtained in the same manner as in Example 45, with the exception that N,N-dimethy1-9H-purin-6-amine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
I H-NMR (500 MHz, Me0D): 6 8.38 (s, 1H), 8.37 (s, IN), 4.41 (t, 2H), 3.98 (br, 2H), 3.56 (t, 1H), 3.42 (br, 31-1), 3.26 (m, I H), 2.97 (m, 2H), 2.19 (m, 5H), 1.78 (in, I H), 1.67 (m, 1H), 1.53 (m, I H) Example 138: Preparation of (2R,3S)-2-(3-(6-(diethylamino)-9H-purin-9-yl)propyl)piperidin-3-ol trihydrochloride õOH
N--/
/
N

The title compound (27 mg, yield: 77%) was obtained in the same manner as in Example 45, with the exception that N,N-diethylarnino-9H-purin-6-amine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
I H-NMR (500 MI-fz, Me0D): 6 8.34 (s, 114), 8.32 (d, 11-1). 4.38 (m. 21-1), 3.66 (br, 41-1), 3.55 (iii, 1H), 3.27 (m, 1H), 2.96 (in, 21-1), 2.14-2.00 (in, 6H), 1.68 (m, 1H), 1.53 (m, 111), 1.38 (br, 6H) Example 139: Preparation of (2R,3S)-2-(3-(6-(ethyl(methypamino)-911-purin-9-yppropyl)piperidin-3-ol trihydrochloride õOH
\N
N

The title compound (28 mg, yield: 78%) was obtained in the same manner as in Example 45, with the exception that N-ethyl-N-methyl-9H-purin-6-amine was used instead of 5-bromo-4-methy1-1H-benzo[djimidazole in step 45-1 of Example 45.
11-1-NMR (500 MHz, Me0D): 6 8.39 (s, 1H), 8.38 (s, 1H), 4.51 (br, 2H), 4.41 (t, 2FI), 3.56 (m, 1H), 3.41 (m, I H), 3.27 (m, 3H), 2.96 (m, 2H), 2.19-1.99 (m, 5H), 1.75 (m, 1H), 1.68 (m, 1H), 1.53 (1, 3H) Example 140: Preparation of (2R,3S)-2-(3-(6-morpholino-911-purin-9-yhpropyl)piperidin-3-ol trihydrochloride _N \N

The title compound (27 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 4-(9H-purin-6-yl)morpholine was used instead of 5-bromo-4-methy1-1111-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 8.35 (s, 1H), 8.33 (d, 1H), 4.39 (m, 214), 3.66 (s, 6H), 3.54 (m, 1H), 3.25 (m, I H), 2.96 (m, 2H), 2.14-1.98 (m, 5H), 1.84 (s, 611), 1.72 (m, 2H), 1.53 (m, 1H) Example 141: Preparation of (2R,3S)-2-(3-(6-(piperidin-1-y0-9H-purin-9-yl)propyl)piperidin-3-ol trihydrochloride /
N

The title compound (30 nig, yield: 81%) was obtained in the same manner as in Example 45, with the exception that 6-(piperidin- I -y1)-9H-purine was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 8.43 (s, 11-1), 8.36 (s, 1H), 4.40 (m, 41-1), 3.91 (m, 41-1), 3.66 (s, 6H), 3.27 (m, I H), 2.96 (m, 2H), 2.03 (in, 5H), 1.69 (m, 2H), 1.53 (m, 1H) Example 142: Preparation of (2R,3S)-2-(3-(6-(pyrrolidin-l-y1)-911-purin-9-yl)propyl)piperidin-3-ol triihydrochloride N
N

The title compound (29 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that 6-(pyrrolidin-l-y1)-91-1-purine was used instead of 5-bromo-4-methyl-IH-benzo[djimidazole in step 45-1 of Example 45.

11-{-NMR (500 MHz, Me0D): 6 8.33 (br, 21-1), 4.37 (in, 41-1), 3.75 (br, 2H), 3.66 (in, 114), 2.96 (in, 2H), 2.17 (br, 61-1), 2.00 (m, 4H), 1.73 (in, 2H), 1.53 (in, 1H) Example 143: Preparation of 1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyI)-1H-benzo[d dihydrochloride HO \F_N
N N

The title compound (25 mg, yield: 79%) was obtained in the same manner as in Example 45, with the exception that 1H-benzo[d]imidazol-2-ol was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): (5 7.16 (d, 11-1), 7.10 (m, 31-0, 3.96 (m, 21-1), 3.53 (m. 1H).
3.20(m, 1H), 2.91 (m, 21-1), 2.00 (m. 5H), 1.62 (m, 2H), 1.51 (m, 1H) Example 144: Preparation of 5,6-dichloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzold limidazol-2-ol dihydrochloride õOHHON
CI

CI
The title compound (27 mg, yield: 84%) was obtained in the same manner as in Example 45, with the exception that 5,6-dichloro-1H-benzo[d]imidazol-2-ol was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
'H-NMR (500 MHz, Me0D): 6 7.38 (s, 1H), 7.21 (s, 11-1), 3.92 (m, 21-1). 3.48 (m, 2H), 3.20 (m, 31-1), 2.89 (m, 3H), 2.04-1.92 (m, 7H), 1.67 (m, 51-1) Example 145: Preparation of (2Rõ3S)-2-(3-(2-(hydroxymethyl)-11-1-benzo[dI itnidazol-1-yl)propyl)piperidin-3-ol dihydrochloride OH
OH N

The title compound (25 mg, yield: 80%) was obtained in the same manner as in Example 45, with the exception that (1H-benzo[d]imidazol-2-yl)methanol was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
11-1-NMR (500 MHz, Me0D): 6 7.99 (d, 1H), 7.81 (d, 1I-1), 7.64 (m, 2H), 5.20 (s, 2H), 4.51 (in, 2H), 3.59 (m, I H), 3.27 (m, I H), 2.97 (m, 2H), 2.20 (m, 11-1), 2.08 (m, 3H), 1.96 (m, 1H), 1.87 (in, 2H), 1.55 (m, IH) Example 146: Preparation of (2R,3S)-2-(3-(2-(hydroxymethyl)-4,5-dimethy1-1H-benzoldlimidazol-1-yl)propyl)piperidin-3-ol dihydrochloride OH
N
N

The title compound (31 mg, yield: 83%) was obtained in the same manner as in Example 45, with the exception that (4,5-dimethy1-1H-benzo[d]imidazol-2-yl)methanol was used instead of 5-bromo-4methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
11-1-NMR (500 MHz, Me0D): 6 7.67 (d, 1H), 7.47 (d, 1H), 5.14 (s. 210, 4.53 (in, 2H), 3.59 (in, 1H), 3.28 (m, I H), 2.97 (m, 2H), 2.57 (s, 3H), 2.47 (s, 3H), 2.20 (m, 1H), 2.10 (m, 3H), 1.97 (m, 1H), 1.76 (in, 2H), l.54 (m. 1H) Example 147: Preparation of (2R,3S)-2-(3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzoldlimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride OH

CI
The title compound (28 mg, yield: 79%) was obtained in the same manner as in Example 45, with the exception that (5,6-dichloro-1H-benzo[d]iinidazol-2-yl)methanol was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, DMSO-d6): 6 8.37 (s, I I I). 7.99 (s, IFI), 4.99 (s, 21-1), 4.40 (in, 21-1), 3.41 (in, 1H), 3.09 (d, 1H), 2.78 (m, 2H), 2.08 (in. I H), 1.98 (m, 2H), 1.89 (m, 1H), 1.77 (m, 1H), 1.64 (m, 2H), 1.35 (m, 1H) Example 148: Preparation of (212,3S)-2-(3-(2-amino-5,6-dichloro-1H-benzoLdJimidazol-1-y1)propyl)piperidin-3-ol dihydrochloride õpH H2N
CI

CI
The title compound (25 mg, yield: 81%) was obtained in the same manner as in Example 45, with the exception that 5,6-dichloro-1H-benzo[d]imidazol-2-amine was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 7.84 (s, IFO, 7.57 (s, IFI), 4.20 (t. 2H), 3.58 (m, I H), 2.97 (m, 1H), 2.98 (m, 2H), 2.07-1.95 (in, 5H), 1.77 (in, 2f1), 1.54 (m, 1H) Example 149: Preparation of methyl 7-bromo-1-(34(2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-carboxylate dihydrochloride 2HCI Br The title compound (30 mg, yield: 75%) was obtained in the same manner as in Example 45, with the exception that methyl 7-bromo-1H-indole-3-carboxylate was used instead of 5-bromo-4-methy1-1H-benzo[d Jimidazole in step 45-1 of Example 45.
I H-NMR (500 MHz. Me0D): 6 8.13 (d. 114), 8.05 (s, 1H), 7.45 (d, 11-1), 7.09 (t, 1H), 4.69 (m, 2H), 3.88 (s, 31-1), 3.48 (m, 1H), 3.16 (m, 1H), 2.88 (n, 2H), 2.00 (m, 514), 1.64 (in, 2H), 1.52 (m, 1H) Example 150: Preparation of methyl 5-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-Apropy1)-1H-indole-3-carboxylate dihydrochloride õOH
Br The title compound (29 mg, yield: 73%) was obtained in the same manner as in Example 45, with the exception that methyl 5-bromo-1H-indole-3-carboxylate was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-1'4MR (500 MHz, Me0D): 6 8.20 (s, 11-1), 8.05 (s, 114), 7.49 (d, IF{), 7.38 (d, 11-1), 4.33 (m, 2H), 3.88 (s, 3H), 3.50 (m, 1H), 3.20 (d, 1H), 2.90 (m, 2H), 1.99 (m, 5H), 1.65 (m, 1H), 1.52 (m, 2H) Example 151: Preparation of methyl 6-bromo-1-(3-((2R,.3S)-3-hydroxypiperidin-2-yl)propy1)-1H-indole-3-carboxylate dihydroch1oride Br The title compound (25 mg, yield: 77%) was obtained in the same manner as in Example 45, with the exception that methyl 6-broino-1H-indole-3-carboxylate was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
H-NNIR (500 MHz, Me0D): 5 8.03 (s, 1H), 7.97 (d, 1H), 7.78 (s, 1H), 7.34 (d, 1H), 4.30 (m, 2H), 3.87 (s, 3H), 3.50 (in, 1H), 3.20 (d, 1H), 2.91 (in, 2H), 1.97 (m, 5H), 1.67 (m, 1H), 1.53 (m, 2H) Example 152: Preparation of methyl 4-chloro-1-(34(211,3S)-3-hydroxypiperidin-2-yl)propy1)-111-indole-3-carboxylate dihydrochloride ci The title compound (27 mg, yield: 70%) was obtained in the same manner as in Example 45, with the exception that methyl 4-chloro-1H-indole-3-earboxylate was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-I\IMR (500 MHz, Me0D): 6 8.07 (s. 1H), 7.51 (d, I H), 7.24 (s, I H), 7.23 (s, 1H), 4.33 (in, 2H), 3.84 (s, 3H), 3.20 (m. 1H), 2.91 (in, 2H), 2.00 (in, 5H), 1.67 (m, 1H), 1.52 (m, 2H) Example 153: Preparation of methyl 6-chloro-1-(3-42R,3S)-3-hydroxypiperidin-2-ybpropy0-1H-indole-3-earboxylate dihydrochloride Cr The title compound (21 mg, yield: 73%) was obtained in the same manner as in Example 45, with the exception that methyl 6-chloro-1H-indole-3-carboxylate was used instead of 5-bromo-4-methyl- I H-benzo[d]imidazole in step 45-1 of Example 45.
'1-1-NMR (500 MHz, Me0D): 6 8.04 (s, 11-e. 8.02 (d, 11-1), 7.62 (s, 1H), 7.21 (d, 11-1).
4.31 (in, 2H), 3.87 (s, 3H), 3.50 On, 11-1), 3.19 (d, 1H), 2.91 (m, 211), 1.97 (n, 5H), 1.65 (in, I H), 1.53 (m, 2H) Example 154: Preparation of methyl 7-chloro-1-(34(2R,3S)-3-hydroxypiperidin-2-ybpropy0-1H-indole-3-carboxylate dihydrochloride 2HCI Cl The title compound (19 mg, yield: 77%) was obtained in the same manner as in Example 45, with the exception that methyl 7-chloro-1H-indole-3-carboxylate was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 8.07 (d, 1H), 8.04 (s, Ii-f), 7.25 (d, 1H), 7.17 0, 111), 4.66 (m, 2H), 3.88 (s, 3H), 3.51 (in, I H), 3.20 (d, 1H), 2.91 (m, 21-1), 3.11 (m, 1H), 2.08 (in, 4H), 1.69 (111, 2H), 1.55 (in, I H) Example 155: Preparation of (2R,3S)-2-(3-(5-chloro-3-cyclopropy1-1H-indazol-1-yl)propyl)piperidin-3-ol dihydrochloride ., H HCI N
CI
HCI
The title compound (20 mg, yield: 65%) was obtained in the same manner as in Example 45, with the exception that 5-chloro-3-cyclopropy1-11-1-indazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
11-1 NMR (500MHz, Me0D): 6 7.93(s, 11-1), 7.47(s, 21-1), 4.35(m, 2H), 3.51(m.
11-f).
3.20(m, 1H), 2.92(m, 21-1), 2.22(m, 1H), 2.10-1.91(m, 41-1), 1.68(m, 11-1), 1.51(m, 2H), 1.04)m, 2H), 0.97(m, 2H) Example 156: Preparation of (2R9.3S)-2-(3-(5-chloro-3-(trifluoromethyl)-1H-indazol-1-yppropyl)piperidin-3-ol dihydrochloride HCIN _ H HCI
The title compound (17 mg, yield: 31%) was obtained in the same manner as in Example 45, with the exception that 5-chloro-3-(trifluoromethyl)-1H-indazole was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in Step 45-1 of Example 45.
NMR (500MHz, Me0D): 6 7.96(s, 1H), 7.72(cl, 1H), 7.65(d, 11-1), 4.57(m. 2I-1).

3.52(m, 1H), 3.22(m, 1H), 2.92(m, 2H), 2.20(m, 11-1), 2.12(m, 1H), 2.00(m, 3H), 1.68(m, 1H), 1.62(m, 1H), 1.50(m, 1K) Example 157: Preparation of (2 R,3S)-2-(3-(5-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-y1)-1H-indazol-1-y1)propyl)piperidin-3-ol dihydrochloride N_N
\ I
OH HCIN
H HCI CI
The title compound (16 mg, yield: 29%) was obtained in the same manner as in Example 45, with the exception that 5-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-y1)-1H-indazole was used instead of 5-bmmo-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
IFI NMR (500MHz, Me0D): 6 8.69(s, 1H), 8.27(s, 1H), 8.03(s, I H), 7.65(d, 114), 7.44(d, 1H), 4.52(m, 2H), 3.50(m, I H), 3.16(m, 1H), 2.90(m, 2H), 2.21(m, 1H), 2.12(m, I H), 2.07(m, 3H), 1.66(m, 2H), I .50(m, 1H) Example 158: Preparation of (2R,3S)-2-(3-(6-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-y1)-1H-indazol-1-yl)propyl)piperidin-3-ol dihydrochloride F,(F
N_N
\
..OH HCIN
/
H HCI
Cl The title compound (17 mg, yield: 30%) was obtained in the same manner as in Example 45, with the exception that 6-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-y1)-1H-indazole was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in Step 45-1 of Example 45.
IH NMR (500MHz, Me0D): 6 8.66(s, 1H), 8.27(s, IF!). 7.99(d, 1H), 7.70(s, 11-1).
7.23(d, 1H), 4.51(m, 2H), 3.50(m, 1H), 3.21(m, 1H), 2.92(m, 2H), 2.18(ni, 1H), 2.10(m, 1H), 2.07(m, 3H), 1 .66(m, 2H), I .55(m. I H) Example 159: Preparation of 1-0-((2R,.3S)-3-hydroxypiperidin-2-yl)propy1)-3-2 0 methyl-1H-benzoldlimidazol-2(3H)-one dihydrochloride The title compound (18 mg, yield: 69%) was obtained in the same manner as in Example 45, with the exception that I -methy1-1,3-dihydro-2H-benzo[d]imidazol-2-one was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazolc in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): 6 7.16 (m, 41-1), 3.99 (m, 2H), 3.66 (s, 2H), 3.53 (m.
2H), 3.43 (s, 3H), 2.94 (m, 2H), 2.00 (m, 4H), 1.88 (m, 1H), 1.62 (m, 2H), 1.52 (m, 1H) Example 160: Preparation of 5-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy0-11-1-benzo[dIhnidazol-2(3H)-one dihydrochloride Br The title compound (15 mg, yield: 42%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
114-1\1MR (500 MHz, Me0D): 6 7.37 (s, 1H), 7.21 (d, 1H), 6.99 (d, 11-1), 3.94 (m, 2H), 3.54 (m, 1H), 3.23 (m, 1H), 2.94 (m, 2H), 2.05-1.87 (in, 511), 1.65 (m, 2H), 1.53 (m, 1H) Example 161: Preparation of 6-bromo-1-(3-02R,3S)-3-hydroxypiperidin-2-Apropy1)-11-1-benzo[d]imidazol-2(311)-one dihydrochloride NH
õOH

Br The title compound (14 mg, yield: 40%) was obtained in the same manner as in Example 45, with the exception that 5-bromo-1,3-dihydro-2H-benzo[d7imidazol-2-one was used instead of 5-bromo-4-methyl-11-1-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz. Me0D): 6 7.23 (d, 1H), 7.22 (s, 11-1), 7.09 (d, 11-1), 3.95 (m, 2H), 3.53 (m, 1H), 3.23 (m, 1H), 2.94 (m. 2H), 2.02-1.87 (m, 5H), 1.66 (in, 2H), 1.53 (in, 1H) Example 162: Preparation of 7-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-1,3-dimethyl-1H-putine-2,6(311,714)-dione dihydrochloride .0 0 \
The title compound (21 mg, yield: 75%) was obtained in the same manner as in Example 45, with the exception that 1,3-dimethy1-3,7-dihydro-1H-purine-2,6-dione was used instead of 5-bromo-4-methy1-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NIVIR (500 MHz, Me0D): 6 8.15 (s, 11-1), 4.40 (br, 214), 3.57 (m, 1H), 3.34 (s, 61-0, 3.26 (m, 1H), 2.98 (in, 2H), 2.00 (m, 5H), 1.72 (m, 2H), 1.55 (m, 1H) Example 163: Preparation of 7-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propy1)-3-methyl-1H-purine-2,6(31-1,7H)-dione dihydrochloride õOH
z N

The title compound (21 mg, yield: 72%) was obtained in the same manner as in Example 45, with the exception that 3-methyl-3,7-dihydro-1H-purine-2,6-dione was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 7.95 (s, 1H), 4.34 (in, 21-), 3.48 (m, 31-1), 3.22 (in. 1H), 2.89 (m, 2H), 1.95 (m, 5H), 1.68 (m, 1H), 1.52 (m, 2H) Example 164: Preparation of 9-(3-((2R.73S)-3-hydroxypiperidin-2-yl)propy1)-1-methyl-1H-purine-2,6(3H,9H)-dione dihydrochloride Fr-N

The title compound (25 mg, yield: 70%) was obtained in the same manner as in Example 45, with the exception that 1-methyl-3,9-dihydro-1H-purine-2,6-dione was used instead of 5-bromo-4-methy1-11-1-benzo[d]imidazole in step 45-1 of Example 45.
1H-NMR (500 MHz, Me0D): 6 7.89 (s, 111), 4.36 (m, 214), 3.66 (m, I H), 3.23 (m, IH), 2.98 (m, 2H), 1.99 (m, 5E-1), 1.69 (m, 114), 1.56 (m, 2H) Example 165: Preparation of 7434(2 R,3S)-3-hydroxypiperidin-2-yl)p ropyI)-3-isobutyl-l-methyl-IH-purine-2,6(3H,711)-dione dihydrochloride õOH
r--0 \
The title compound (25 mg, yield: 70%) was obtained in the same manner as in Example 45, with the exception that 3-isobutyl- -methy1-3,7-dihydro- 1 H-purine-2.6-dione was used instead of 5-bromo-4-methyl-1H-benzo[d]imidazole in step 45-1 of Example 45.
H-NMR (500 MHz, Me0D): (57.95 (s, 1E-1), 4.38 (m, 2H), 3.90 (m, 3H), 3.54 (m, 114), 3.36 (m, 4H), 3.28 (m, 1H), 2.99 (in, 21-1), 2.26 (m, 1H), 2.04 (in, 5H), 1.69 (m, 1H), 1.63 (m, 1E1), 1.54 (m, 1H), 0.94 (m, 8H) Example 166: Preparation of (2R,3S)-24(E)-3-(5,6-dichloro-11-1-benzo[dJimidazol-1-Aprop-1-enyl)pipetidin-3-ol dihydrochloride r---CI

CI
Step 166-1: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-24(E)-3-ethoxy-3-oxoprop-1-en-l-yl)piperidine-t-carboxylate Methylene chloride (47 mL, 0.12 M) and oxalyl chloride (1.0 mL, 11.6 minol) were added to a flask tilled with nitrogen and the reaction solution was cooled to -78'C.
Dimethylsulfoxide (1.7 mL, 23.2 mmol) was then added at the same temperature and stirred for minutes. Then, tert-butyl (2R,3S)-3-((tert-butyldirnethylsilyl)oxy)-2-(hydroxyrnethyl)piperidine-1-carboxylate (2.0 g, 5.8 mmol) was dissolved in a small amount of 25 methylene chloride and slowly added. After stirring at the same temperature for 1 hour, triethylamine (3.3 inL, 23.2 mmol) was added and the temperature of the reaction solution was raised to room temperature from -78 C. When the reaction was completed, the solvent was removed, and the resuolting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried with magnesium sulfate, filtered and concentrated under reduced pressure, and then dissolved in methylene chloride (47 mL, 0.12 M). Then, (carbethoxymethylene)triptienylphosphorane (4.0 g, 11.6 mmol) was added thereto and stirred for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and then concentrated under reduced pressure, and purified by column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (2.1 g, yield: 89%).
Step 166-2: Preparation of (E)-3-((2R,3S)-1-(tert-butoxycarbonyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-2-yl)acrylic acid Tert-butyl (2R,3 S)-3 -((tert-butyldimethylsi lyl)o xy)-2-((E)-3 -ethox y-3 -oxoprop-1-en-1-yl)piperidine-l-earboxylate (3.0 g, 7.2 mmol) obtained from Step 166-1 was dissolved in methanol (20 mL, 0.36 mmol). Then, 2N sodium hydroxide aqueous solution (10 mL) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction solution was neutralized with IN aqueous hydrochloric acid solution, acidified, diluted with ethyl acetate and then washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 166-3: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-24(E)-3-hydroxyprop-en-1-yl) piperidine-l-carboxylate (E)-3-((2R,3S)-1-(tert-butoxycarbony1)-3-((tert-butyldimethylsily1)oxy)piperidin-2-ypacrylic acid (1.6 g, 4.0 mmol) obtained from Step 166-2 was dissolved in tetrahydrofuran (50 mL, 0.08 M), and the reaction solution was cooled to 0 C. Then, a lithium aluminum hydride solution (1.6 mL, 4.0 mmol) was slowly added thereto, reacted at the same temperature for 30 minutes and then stirred at room temperature for 2 hours. A small amount of water was added to 3 0 complete the reaction, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (diehloromethane:
methanol = 10:1) to give the title compound (1.3 g, yield: 85%).
Step 166-4: Preparation of tert-butyl (2R,3S)-24(E)-3-bromoprop-1-en-1-y1)-3-((tert-butyldimethylsilypoxy)piperidine-1-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-24(E)-3-hydroxyprop-en-l-yl)piperidine- 1 -carboxylate (100 mg, 0.27 mmol) obtained from Step 166-3 was added to methylene chloride (10 mL, 0.03 M). The reaction solution was cooled to 0 C, and then triphenylphosphine (106 g, 0.40 mmol) and tetrabromomethane (134 mg, 0.40 mmol) were sequentially added at the same temperature, followed by stirring at room temperature for 2 hours.
When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 5:1) to give the title compound (89 mg, yield: 76%).
Step 166-5: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-24(E)-3-(5,6-dichiloro-IH-benzo[d]irnidazol-1-y1)prop-1-en-1-y1)piperidine-1-carboxylate Tert-butyl (2R,3S)-24(E)-3-bromoprop-1-en-l-y1)-3-((tert-butyldimethylsilyl)oxy)pipendine-1-carboxylate (83 mg, 0.19 mmol) obtained from Step 166-4 was dissolved in N,N-dirnethylformamide (3 mL, 0.06 M). Potassium carbonate (53 mg, 0.38 mmol) and 5,6-dichloro-1H-benzo[d]imidazole (35 mg, 0.19 mmol) were added thereto and the mixture was stirred at room temperature for 4 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 1:2) to give the title compound (88 g, yield: 85%).
Step 166-6: Preparation of (2R,3S)-2-(( E)-3--(5,6-d ichloro-11-1-bergo [d]im idazol-yl)prop-1-en-l-y1)piperidin-3-ol dihydrochloride Tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-24(E)-3-(5,6-dichloro-1H-benzo[d] im idazol-1-y1)prop-1-en-1-y1)piperidine-1-carboxyl ate (85 mg, 0.16 mmol) obtained from Step 166-5 was dissolved in a small amount of tetrahydrofuran. Then, 4N
hydrogen chloride dioxane solution (5 mL, 0.03 M) was added thereto and stirred at room temperature for 12 hours.
When the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved by addition of a small amount of methanol and then crystallized with diethyl ether to obtain the title compound (51 mg, yield: 81%).
H-N-MR (500 MHz, DMSO-d,5) : 6 8.86 (s, 1H), 8.12 (s. 111), 8.04 (s, 1H), 6.11 (dt,1H), 5.85 (d, 1H), 5.03 (d, 2H), 3.54 (m, 1H), 3.40 (in, I H), 3.13 (d, 1H), 2.79 (m, I H), 1.94 (m, I H), 1.79 (d, 1H), 1.68 (in, 1H), 1.41 (m, 1H) Example 167: Preparation of (2 R,38)-24(E)-3-(5-fluoro-4-niethyl-1 H-benzo ldlimidazol-1-y1)prop-1-enyl)piperidin-3-ol dihydrochloride The title compound (24 rag, yield: 80%) was obtained in the same manner as in Example 166, with the exception that 5-fluoro-4-methyl-1H-benzo[dlirnidazole was used instead of 5,6-dichloro-I H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 9.45 (d. 1H), 7.73 (m, 1H), 7.42 (m, 1H), 6.25 (m, 1H), 5.98 (m, I H), 5.23 (s, 2H), 3.55 (in, 2H), 2.96 (m, 1H), 2.56 (s, 31-1), 2.00 (m, 3H), 1.74 (m, 11-f), 1.56(m, 1H) Example 168: Preparation of (2R,38)-24(E)-3-(5-bromo-4-methyl-1H-benzoldlimidazol-1-y1)prop-1-enyppiperidin-3-ol dihydrochloride N
2HCI Br The title compound (30 mg, yield: 85%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-4-methyl-11-1-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 9.38 (d. 1H), 7.68 (m, 11-1), 7.37 (in, 11-1), 6.15 (m, 1H), 5.88 (m, 1H), 5.00 (s, 2H), 3.34 (in, 2H), 2.78 (m, 1H), 2.54 (s, 3H), 1.97 (m, 3H), 1.68 (in, 1H), 1.48(m, 1H) Example 169: Preparation of (2 R,3S)-24(E)-3-(5,6-dimethyl-1H-benzo[di imidazol-1-yl)prop-1-en-1-yppiperidin-3-ol dihydrochloride ,,OH

The title compound (30 mg, yield: 85%) was obtained in the same manner as in Example 166, with the exception that 5,6-dimethy1-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, IVIe0D): 6 7.64 (m, 11-1), 7.61 (s, 1H), 6.25 (m, 11-1), 5.91 (m, Ii-f), 5.20 (s, 21-1), 3.56 (in, 21-f), 2.95 (in, 1H), 2.46 (in, 1H), 2.45 (s, 614), 2.09 (m, 2.00 (m, 2H), 1.72 (m, 1H), 1.56 (m, 1H) Example 170: Preparation of (2R,3S)-24(E)-3-(5,6-dibromo-11-1-benzo[dlimidazol-1-yl)prop-1-en-1-yl)piperidin-3-oldihydrochloride Br Br The title compound (24 mg, yield: 80%) was obtained in the same manner as in Example 166, with the exception that 5,6-dibromo-1H-benzo[dlimidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): (59.21 (m, 1H), 8.30 (in, 1H), 8.21 (m, 1H), 6.22 (m.
1H), 5.92 (m, 1H), 5.16 (in, 211), 3.56 (m, 2H), 2.95 (m, 1H), 1.99 (n, 3H), 1.72 (in, 1H), 1.56 (m, 1 1-1) Example 171: Preparation of (2R,3S)-24(E)-3-(5,6-difluoro-1H-benzo[djimidazol-1-yl)prop-1-en-1-Apiperidin-3-ol dihydrochloride (09 õOH
N

The title compound (20 mg, yield: 86%) was obtained in the same manner as in Example 166, with the exception that 5,6-ditluoro-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 7.76 (m, I Fe, 6.22 (in, 1H), 5.88 (m, 1H), 5.12 (tn, 2H), 3.57 (m, 3H), 2.92 (m, 1H), 2.20 (m, 4H), 1.72 (m, 1H), 1.56 (m, 1H) Example 172: Preparation of (2R,3S)-2-0E)-3-(4,5-dimethyl-1H-benzoidlimidazol-1-y1)prop-1-en-1-y1)piperidin-3-ol dihydrochloride ,,OH N

The title compound (19 mg, yield: 81%) was obtained in the same manner as in Example 166, with the exception that 4,5-dimethy1-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz, Me0D): 6 9.42 (m, 11 I), 7.62 (m, 1H), 7.47 (m, 11-1). 6.25 (ni, 1H), 5.94 (in, 1H), 5.21 (ni, 2H), 3.55 (m, 2H), 3.34 (m, 1H), 2.95 (in, 1H), 1.99 (m, 2H), 1.74 (m, I H), 1.53 (m, 1H) Example 173: Preparation of (2R93S)-24(E)-3-(5-chloro-4-methyl-11-1-benzo imidazol-1-yl)prop-I-en-l-y1)piperidin-3-ol hydrochloride , õOH
N

The title compound (25 mg, yield: 82%) was obtained in the same manner as in Example 166, with the exception that 5-chloro-4-methyl-11-1-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[diimidazole in Step 166-5 of Example 166.
11-1-NMR (500 MHz, Me0D): 69.50 (s, 1H), 7.76 (d. 1H), 7.67 (d, 11-1), 5.98 (m, 1H).
5.23 (in, 2H), 3.63 (in, I H), 3.55 (in, I H). 2.96 (m, I H). 2.66 (s, 3H), 2.09 (m, 1H), 2,00 (m, 11-1), Ito 1.74 (m, 1H), 1.53 (m, 111) Example 174: Preparation of (2R,3S)-24(E)-3-(4,5-clichloro-IH-benzoldlimidazol-1-y1)prop-1-en-1-ybpiperidin-3-ol dihydrochloride ,OH r,N CI
HCI HCI CI
The title compound (20 mg, yield: 89%) was obtained in the same manner as in Example 166, with the exception that 4,5-dichloro-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1 NMR (500MHz, Me0D): 3 9.58(s, 1H), 7.91(d, 11-1), 7.79(d, 1H), 6.30(m.
1H), 6.03(m, 1H), 5.25(d, 2H), 3.69(m, H), 3.58(m, 1H), 3.01(m, 11-1), 2.11(m, 1H), 2.03(m, 1H), 1.80(m, 1H), 1.55(m, 11-1) Example 175: Preparation of (2R,3S)-24(E)-3-(4-chloro-5-methyl-111-benzoldlimidazol-1-ybprop-1-en- 1 -yl)piperidin-3-ol dihydrochloride r:---"N CI
/
HCI HCI
The title compound (23 mg, yield: 91%) was obtained in the same manner as in Example 166, with the exception that 4-chloro-5-methyl-11-1-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1 NMR (500MHz, Me0D): 8 9.52(s, 1H), 7.88(d, I H), 7.70(d, 1H), 6.25(m, 1H), 6.01(m, 1H), 5.20(d, 2H), 3.62(m, Ii-I), 3.49(m, 1H), 3.00(m, 1H), 2.65(s, 31-1), 2.05(m, 1H), 2.00(m, 1H), 1.74(m, 1H), 1.51(m, 1H) Example 176: Preparation of (2R.,3S)-24(E)-3-(5-bromo-4-nitro-IH-benzoidlitnidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride HCI HCI Br I I I

The title compound (9 mg, yield: 45%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-4-nitro-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H NMR (500MHz, Me0D): 6 8.94(s, 1H), 7.93(d, 1H), 7.83(d, 1H), 6.27(m, 1H), 5.84(m, I H), 5.20(m, 2H), 3.62(m, 2H), 3.58(m 1H), 2.99(m, 1H), 2.1 1 (rn, 1H), 2.08(m, 1H), 1.98(m, 1H), 1.59(m, 1H) Example 177: Preparation of (2R,3S)-24(E)-3-(6-bromo-7-nitro-11-1-benzo[dlimidazol-1-yl)prop-1-eri-1-yl)piperidin-3-ol dihydrochloride N
H HCI HCI
02N Br The title compound (10 mg, yield: 51%) was obtained in the same manner as in Example 166, with the exception that 5-brotno-4-nitro-1H-benzo[dlimidazole was used instead of 5,6-dichloro-1H-bervo[d]imidazole in Step 166-5 of Example 166.
NMR (500MHz, Me0D): 6 8.45(s, 1H), 7.85(d, 1H), 7.69(d, 1H), 6.11(m, 1H), 5.59(m, 1H), 4.28(m, 2H), 3,62(m, 2H), 2.96(m 1H), 2.24(m, 1H), 1.72(m, 2H), 1.58(m, 1H), 1.53(m, 1H) Example 178: Preparation of (2R,3S)-24(E)-3-(4-chloro-5-nitro-11-1-benzo[dlimidazol-1-yl)prop-I-en-1-y1)piperidin-3-ol dihydrochloride ,,OH N ci N

The title compound (II mg, yield: 52%) was obtained in the same manner as in Example 166, with the exception that 4-chloro-5-nitro-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1 NMR (500MHz, Me0D): 6 9.06(s, 1H), 8.04(m, 114), 7.92(m, 1H), 7.87(m, 111).
6.26(m, 1H), 5.86(m, H), 5.26(m, 2H), 3.60(m, 2H), 2.96(m, 2H), 2.07(m, 1H), I
.99(m 2H), 1.77(m, 1H), I.51(m, 1H) Example 179: Preparation of (21,3S)-24(E)-3-(4,6-difluoro-1H-benzo[diimidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride ,,OH _N F
HCI HCI
The title compound (15 mg, yield: 62%) was obtained in the same manner as in Example 166, with the exception that 4,6-difluoro-1H-benzo[d]imidazole was used instead of 5,6-diehloro-114-benzo[d]imidazole in Step 166-5 of Example 166.
11-1 NMR (500MHz. Me0D): (39,22(m, 1H), 7.58(m, 1H), 7.32(m, 11-1), 6.38(m, 114), 5.99(m, 1H), 5.27(d, 1H), 3.65(m, 2H), 2.99(t, 1H), 2.19(m, 1H), 2.08(m, 2H), 1.87(m, 2H), 1.65(m, 1H) Example 180: Preparation of (2R,3S)-24(E)-3-(6-chloro-4-methyl-1H-benzo[d]imidazol-1-y1)prop-1-en-1-yppiperidin-3-ol dihydrochloride õOH N
I
HCI HCI
CI
The title compound (14 mg, yield: 58%) was obtained in the same manner as in Example 166, with the exception that 6-chloro-4-methyl-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1F1 NMR (500MHz, Me0D): (39,53(m, 1H), 7.85(m, 1H, 7.50(m, 1H), 6.31(m, 1H), 6.01(m, 1H), 5.41(m, I H), 3.66(m, 1H), 3.00(m. 2H), 2.64(s, 3H), 2.08(m, 311), 1.73(m, 1H) Example 181: Preparation of (2R93S)-24(E)-3-(7-chloro-5-(trifluoromethyl)-111-benzo[d]imidazol-1-yl)prop-1-en-1-y1)piperidin-3-oldihydrochloride õOH r__N

HCI
CI
The title compound (19 mg, yield: 75%) was obtained in the same manner as in Example 166, with the exception that 7-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
114 NMR (500MHz, Me0D): 6 9.51(m, 11-1), 8.20(m, IN, 7.99(m, 1H), 6.37(m, 1H).
5.89(m, 1H), 5.47(m, 2H), 3.59(m, 2H), 2.93(m, 1H), 2.08(m, 2H), 2.06(m, 114), 1.75(m, 1H), 1.58(m, 1H), 1.51(m, 11-1) Example 182: Preparation of (2R,3S)-24(E)-3-(5,7-dichloro-1H-benzo[dJimidazol-1-yl)prop-1-en-1-yl)piperidin-3-oldihydrochloride õOH
HCI HCI CI
CI
The title compound (22 mg, yield: 85%) was obtained in the same manner as in Example 166, with the exception that 5,7-dichloro-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[dlimidazole in Step 166-5 of Example 166.
IFI NMR (500M1-Iz, Me0D): 6 9.04(s. 114), 7.81(s. 11-1), 7.61(s, 1H), 6.36(m, 1H), 5.74(m, 1H), 5.42(m, 11-i). 3.63-3.53(m, 21-1), 2.99(m, 1H), 2.09(m. 1F1), 2.01(m, 1H), 1.76(m, 1H), 1.59(m, 1H), 1.51(m, 1H) Example 183: Preparation of (2R,3S)-24(E)-3-(5-chloro-7-fluoro-114-benzo[dlimidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride N
H HCI HCI Cl The title compound (18 mg, yield: 72%) was obtained in the same manner as in Example 166, with the exception that 5-chloro-7-fluoro-1H-benzo[d]iinidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1 N-MR (500MHz, Me0D): 6 9.56(s, 111), 7.75(m, 1E4 7.47(m. 1H), 6.33(m, 11-1), 6.02(m, 1H), 5.28(m, 21-1). 3.66(m, 2H), 2.99(m, 1H), 2.11(m, 21-1). 1.78(m, 2H), 1.55(m, 1H) Example 184: Preparation of (2 R,3S)-2-((E)-3-(5-bromo-111-imidazof 4,5-b)pyridin- 1 -yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride N
r--/ 2HCI Br The title compound (18 mg, yield: 40%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-1H-imidazo[4,5-b]pyridine was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NIMR (500 MHz, Me0D): 6 8.37 (s, 11-1), 7.94 (m, 1H), 7.46 (m, 1H), 6.24 (m, 1H), 5.70 (m, I H), 5.08 (m, 2H), 3.49 (m, 2H), 3.24 (m, 11-1), 2.91 (m, I H), 1.97 (in, 2H), 1.68 (m, 1H), 1.51 (in, 1H) Example 185: Preparation of (2R,3S)-24(E)-3-(7-ehloro-6-(3-ehlorophenyl)-3H-1 0 imidazo[4,5-bIpyridin-3-yl)prop-1-en-l-Apiperidin-3-ol dihydrochloride N
CI
Cl The title compound (20 mg, yield: 41%) was obtained in the same manner as in Example 166, with the exception that 7-chloro-6-(3-chloropheny1)-3H-imidazo[4,5-b]pyridine was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 8.52 (s, 1H), 8.38 (s. 1H), 7.42 (m, 414), 6.26 (m, 11-1), 5.68 (m, 11-1), 5.12 (in, 2H), 3.51 (m, 2H), 3.34 (m 1H), 2.92 (m, I H), 1.99 (m, 2H), 1.53 (in, 214) Example 186: Preparation of (2R,3S)-24(E)-3-(6-bromo-7-methyl-311-imidazo[4,5-bjpyridin-3-yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride I N
N Br The title compound (18 mg, yield: 40%) was obtained in the same manner as in Example 166, with the exception that 6-bromo-7-methy1-3H-imidazo[4,5-blpyridine was used instead of 5,6-dichloro-IH-benzo[d]imidazole in Step 166-5 of Example 166.
11-1-1\I4R (500 MHz. Me0D): 6 8.39 (s, 1H), 8.34 (s, 1H), 6.24 (in, 1H), 5.70 (m, 11-f), 5.08 (in, 2H), 3.49 (m, 2H), 3.24 (in, 1H), 2.91 (in, I H), 2.23 (s, 3F-1), 1.97 (in, 2H), 1.68 (m, 1H), 1.51 (m, 1H) Example 187: Preparation of (2R,3S)-2-((E)-3-(6-bromo-7-chloro-311-imidazo [4,5-bipyridin-3-yl)prop-1-en-1-y1)piperidin-3-ol dihydrochloride ,,OH N
CI
N¨ Br The title compound (25 mg, yield: 45%) was obtained in the same manner as in Example 166, with the exception that 6-bromo-7-chloro-3H-irnidazo[4,5-b]pyridine was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
IH-NMR (500 MHz, Me0D): -8 8.58 (in, 2H), 6.24 (m, 114), 5.70 (m, 114), 5.08 (m. 2H), 3.49 (m, 2H), 3.24 (in, 1H), 2.91 (m, 11-1), 1.97 (in, 214), 1.68 (m, 111), 1.51 (m, 1F1) Example 188: Preparation of (2R,3S)-24(E)-3-(6-chloro-7-methyl-311-imidazo14,5-b I pyridin-3-yl)prop-1-en-1-yl)piperidin-3-ol dihydrochloride N CI
= 2HCI
The title compound (32 nig, yield: 84%) was obtained in the same manner as in Example 166, with the exception that 6-chloro-7-methyl-3H-imidazo{4,5-bipyridine was used instead of 5,6-dichloro-11-i-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz, Me0D): 8 8.37 (s, 1H), 8.31 (s, 1H), 6.22 (m, 1H), 5.68 (in, 1H), 5.06 (m, 2H), 3.38 (m, 214), 3.20 (n, IH), 2.84 (in, 1H), 2.20 (s, 314), 1.87 (in, 2H), 1.54 (in, I H), 1.48 (in, 1H) Example 189: Preparation of (2R,3S)-24(E)-3-(6,7-dichloro-3H-imidazo[4,5-131pyridin-3-yl)prop-1-en-l-yl)piperidin-3-ol dihydrochloride CI
\
CI

The title compound (25 mg, yield: 60%) was obtained in the same manner as in Example 166, with the exception that 6,7-dichloro-311-imidazo[4,5-b]pyridine was used instead of 5,6-diehloro-11-1-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz, DMSO-do): 6 8.68 (s, 1H), 8.57 (s, 1H), 6.15 (dd, 1H), 5.76 (dd, I H), 4.98 (d, 2H), 3.52 (m, 1H), 3.40 (m, 11-1), 3.09 (d, 1H), 2.78 (dd, I
H), 1.92 (m, 111), 1.77 (m, 1H), 1.68 (m, 1H), 1.37 (m, 1H) Example 190: Preparation of (2 R,3S)-24(E)-3-(6-(3-chloropheny1)-1 H-benzo [d imid azol-1-yl)p rop-1-en-1-yl)piperidin-3-ol dihyd roc hlo ride õOH
N

/
CI
The title compound (18 mg, yield: 40%) was obtained in the same manner as in Example 166, with the exception that 6-(3-chloropheny1)-1H-benzo[d]imidazole was used instead of 5,6-dich1oro-IH-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz. Me0D): 6 9.53 (s, 1H), 8.18 (s. 11-1). 7.96 (s, 214), 7.80 (s, 111).
6.69 (d, 1H), 7.50 (t, 111), 7.45 (d, 1H) 6.34 (dd, 1H), 6.00 (dd, 1H), 5.32 (d, 2H), 3.64 (m, 2H).
2.97 (m, 11-1), 2.10 (m, 1H), 1.98 (m, 11-1), 1.75 (in, 1H), 1.56 (in, 114), 1.30 (m, 1K) Example 191: Preparation of (2 R,3S)-2-((E)-3-(6-(3-fluorop lieny1)-1 H-benzoldlimidazol-1-y1)prop-1-en-1-y1)piperidin-3-ol dihydrochloride õOH

The title compound (15 mg, yield: 42%) was obtained in the same manner as in Example 166, with the exception that 6-(3-fluorophenyl)-1 H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I EI-NMR (500 MI lz. Me0D): 6 9.35 (s, 111), 8.23 (d. 1H), 7.93 (s, 21-1), 7.57 (d, 1H), 7.52 (d, 2H), 7.17 (t. 1H), 6.32 (d, 1H), 5.94 (m, 1H), 5.31 (rn, 2H), 3.56 (in, 3H), 2.97 (m, 1H), 2.10 (m, 11-1), 2.01 (in, 1H), 1.72 (m, 1H), 1.55 (m, 1H) Example 192: Preparation of (2R,.3S)-24(E)-3-(6-(3-(trifluoromethyl)pheny1)-1H-benzoldlimidazol-1-y1)prop-1-enyppiperidin-3-ol dihydrochloride The title compound (15 mg, yield: 40%) was obtained in the same manner as in Example 166, with the exception that 6-(3- (tritluoromethyl)pheny1)-114-benzo[d]imidazole was used instead of 5.6-dichloro-1H-buizotdiimidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 9.48 (s, 114), 8.21 (s, 1H), 8.03 (m, 2H), 8.01 (s, 214).
7.73 (m, 2H), 6.34 (td, 1H), 5.99 (dd, 1H), 5.34 (m, 2H), 3.60 (td, 2H), 2.95 (m, 114), 2.10 (d. 1H), 2.01 (d, 1H), 1.74(m, H), 1.55 (m, 114), 1.31 (m, 1H) Example 193: Preparation of (2R,3S)-24(E)-3-(5-bromo-6,7-difluoro-2-methyl-1H-benzoldlimidazol-1-y1)prop-I-en-l-y1)piperidin-3-ol dihydrochloride Br The title compound (12 mg, yield: 40%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-6,7-difluoro-2-methyl-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
'H-MR (500 MHz, Me0D): 6. 8.37 (s, 1H). 8.31 (s, 111), 6.22 (m, 1H), 5.68 (m, 1H), 5.06 (m, 2H), 3.38 (m, 214), 3.20 (in, 1H), 2.84 (m, I H), 2.20 (s, 3H), 1.87 (m, 2H), 1.54 (m, 1H), 1.48 (m, 1H) Example 194: Preparation of (2F0S)-2-((E)-3-(indolin-l-ypprop-1-en-1-y1)piperidin-3-ol dihydrochloride The title compound (25 mg, yield: 80%) was obtained in the same manner as in Example 166, with the exception that indoline was used instead of 5,6-dichloro-1H-benzordlimidazole in Step 166-5 of Example 166.
1H-NMR (500 MIL, Me0D): 6 7.29 (m, 4E0, 6.89 (s, 21-0, 4.14 (m, 2H), 3.82 (m, 3.56 (m, 2H), 3.25 (m, 5H), 2.95 (m, 1H), 1.99 (m, 2E0, 1.74 (in 1H), 1.56 (m, 1H) Example 195: Preparation of (2R,3S)-2-((E)-3-(5-chloroindolin- 1-yl)prop-1-en-yl)piperidin-3-ol dihydrochloride N
CI

The title compound (27 mg, yield: 82%) was obtained in the same manner as in Example 166, with the exception that 5-chloroindoline was used instead of 5,6-dichloro-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 7.10 (s. 11-1), 6.89 (in, 21-1), 6.04 (s, 2H), 4.12 (m. 21-0, 3.74 (m. 2H), 3.42 (m, 2H), 3.20 (m, 5H), 2.84 (in, 1H), 1.97 (m, 2H), 1.68 (m, 1H), 1.52 (m, 114) Example 196: Preparation of (2R93S)-2-0E)-3-(1H-pyrrolo[2,3-bjpyridin-1-yllprop-1-en-1-y1)piperidin-3-ol dihydrochloride õOH
N

The title compound (30 mg. yield: 80%) was obtained in the same manner as in Example 166, with the exception that 1H-pyrrolo[2,3-b]pyridine was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz. Me0D): 6 8.21 (d, 11-1), 7.98 (in, II-0, 7.37 (m. 11-1), 7.09 (m. 114), 6.51 (in, 1H), 6.20 (in, 111), 5.90 (in. 11-1), 4.87 (m, 2H), 3.61 (in, 111), 3.52 (in, 1H), 3.27 (in, 1H), 2.95 (m, 1H), 2.00 (in, 2H), 1.71 (m, 11-1), 1.56 (in, 1H) Example 197: Preparation of (21R,.3S)-24(E)-3-(6-chloro-11-1-indol-1-yl)prop-1-en-1-y1)pipericlin-3-ol dihydrochloride CI
The title compound (37 mg, yield: 83%) was obtained in the same manner as in Example 166, with the exception that 6-chloro-1H-indole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 67.36 (m, 3H), 7.08 (d, 1H), 6.90 (m, 1H), 6.13 (m, 1H).
5.38 (m, IH), 4.87 (in, 2H), 3.44 (m, 2H), 3.15 (m, 1H), 2.88 (m, 1H), 1.94 (m, 2H), 1.65 (m, 1H), 1.48 (m, 1H) Example 198: Preparation of (2 R,3S)-2-((E)-3-(6-chloro-1H-indazol-1-y1)prop-1-en-1-yl)piperidin-3-ol dihydrochloride ,,OH
N--CI
The title compound (25 mg, yield: 79%) was obtained in the same manner as in Example 166, with the exception that 6-chloro-1H-indazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 68.02 (s, I H), 7.71 (m. 1H), 7.63 (s, Ili), 7.12 (m, 1H), 6.20 (m, I H), 5.62 (in, I H), 5.21 (m 2H), 3.54 (tn, 1H), 3.46 (m, 1H), 3.22 (m, 1H), 2.90 (m, 1H), 2.05 (m, 1H), 1.96 (in, 1H), 1.65 (m, 11-1), 1.50 (m, 1H) Example 199: Preparation of (2R,3S)-2-0E)-3-(41-chloro-7H-pyrrolo12,3-dipyrimidin-7-y1)prop-1-en-1-y1)piperidin-3-ol dihydrochloride, OH
----- CI
N

The title compound (27 mg, yield: 85%) was obtained in the same manner as in Example 166, with the exception that 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was used instead of 5,6-diehloro-1H-benzo[d]imiclazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 8.53 (s, III), 7.60 (s, 11-1), 6.69 (m, 1H), 6.18 (m. 1H), 5.53 (m, 1H), 5.04 (in, 2E1), 3.46 (m, 2H), 3.21 (m, 114), 2.90 (m, 1H), 1.96 (m, 2H), 1.56 (m, 11-I), 1.50(m, 1H) Example 200: Preparation of (2R,3S)-24(E)-3-(5-chloro-1H-pyrazolo[3,4-b]pyridin-l-y1)prop-1-en-1-y1)piperidin-3-ol dihydrochloride N

The title compound (25 mg, yield: 81%) was obtained in the same manner as in Example 166, with the exception that chloro-1H-pyrazolo[3,4-b]pyridine was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz. Me0D): 6 8.52 (m, IN), 8.26 (m, 11-1), 8.13 (s, 1H), 6.20 (m, 1H), 5.62 (m, 1H), 5.21 (m 2H), 3.54 (in, 1H), 3.46 (in, 1H), 3.22 (in, I H), 2.90 (in, 1H), 2.05 (m, 1H), 1.96 (m, I H), 1.65 (in. I H), 1.50 (m. 1H) Example 201: Preparation of (2R,3S)-24(E)-3-(3,5-dimethy1-111-indazol-1-yl)prop-1-en-l-yl)piperidin-3-ol dihydrochloride OH

The title compound (28 mg, yield: 79%) was obtained in the same manner as in Example 166, with the exception that 3,5-dimethy1-1H-indazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz, Me0D): 6 7.74 (s, 1H), 7.50 (m, 114), 7.37 (in. 1H), 6.13 (m, 1H), 5.49 (in, 1H), 5.02 (m, 2H), 3.50 (m, 1H), 3.44 (m, 11-1), 3.32 (s, 3H), 3.21 (m, 1H), 2.90 (in, 1H), 2.51 (s, 3H), 2.04 (m, I H). 1.95 (in, 1H), 1.56 (in, 111), 1.49 (in, 111) Example 202: Preparation of methyl 7-bromo-H(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylate dihydrochloride Br The title compound (30 mg, yield: 82%) was obtained in the same manner as in Example .. 166, with the exception that methyl 7-bromo-1H-indole-3-carboxylate was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1-NMR (500 MHz, Me0D): 6 8.14 (m, 1H), 8.04 (s, 1H), 7.44 (m, 1H), 7.09 (m, 114), 6.26 (m, 1H), 5.43 (m, 1H), 5.31 (m, 1H), 3.50 (m, 2H), 3.15 (m, 1H), 2.88 (m, 1H), 1.94 (m, 2H), 1.62 (m, 1H), 1.50 (m, 1H) Example 203: Preparation of 7-bromo-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid dihydrochloride OH

Br The title compound (28 mg, yield: 80%) was obtained in the same manner as in Example .. 166, with the exception that 7-bromo- 1 H-indole-3-earboxylic acid was used instead of 5,6-diehloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I H-I\ITVIR (500 MHz, Me0D): 6 8.02 (m, 2H), 7.39 (d, EH), 7.09 (m, 11-1), 6.21 (m, 11-1), 5.91 Om 1K), 4.83 (m, 2H). 3.62 (m, I H), 3.51 (in, 1H), 3.26 (m, I H), 2.94 (m, 1H), 1.98 (m, 2H), 1.71 (m, 1H), 1.52 (in, 1H) Example 204: Preparation of 5-bromo-1-0E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-111-indole-3-carboxylic acid dihydrochloride OH
2HCI Br The title compound (35 mg, yield: 82%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-1H-indole-3-carboxylic acid was used instead of 5,6-dichloro-I H-benzo[d]im idazole in Step 166-5 of Example 166.
(5001V[Hz, Me0D): 6 8.18 (s, 11-1), 8.01 (m, 114), 7.31 (m, 2H), 6.21 (m, 1H), 5.90(m, I H), 4.89 (m, 2H), 3.61 (m, 1H), 3.53 (m, 1H),3.23 (in, 1H), 2.95 (m, 11-1), 1.99 (m, 2H), 1.68 (m, 1H), 1.53 (m, 1H) Example 205: Preparation of 4-chloro-14(E)-34(2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid dihydrochloride OH
OH
¨ CI

The title compound (31 mg, yield: 83%) was obtained in the same manner as in Example 166, with the exception that 4-chloro-1H-indolc-3-carboxylic acid was used instead of 5,6-dichloro-11-1-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 8.06 (s, 1H), 7.41 (d, 1H), 7.15 (m, 21-1), 6.20 (m, 1H), 5.90 (in, 1H), 4.87 (in, 21-1), 3.61 (m, I H), 3.52 (m, 1H), 3.27 (m, 1H), 2.95 (m, 11-1), 2.00 (in, 2H), 1.71 (in, 1H), 1.56 (in, 1H) Example 206: Preparation of 6-chloro-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid dihydrochloride OH

CI
The title compound (27 mg, yield: 79%) was obtained in the same manner as in Example 166, with the exception that 6-chloro-1H-indole-3-carboxylic acid was used instead of 5.6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
114-1\1MR (500 MHz, Me0D): 68.01 (d, 114), 7.46 (m. 114), 7.17 (d, 1H), 6.22 (m, 114), 5.91 (in, 1H), 4.88 (m, 2H), 4.36 (in, 1H), 3.61 (m, 1H), 3.27 (in, 1H), 2.94 (m, 1H), 2.05 (in, 2H), 1,72 (m, 1H), 1.56 (m, 1H) Example 207: Preparation of 7-chloro-k(E)-3-((2R93S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid dihydrochloride OH
N

The title compound (25 mg, yield: 77%) was obtained in the same manner as in Example 166, with the exception that 7-chloro-1H-indole-3-carboxylic acid was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
IH-NMR (500 MHz, Me0D): 68.00 (m, 2H), 7.16 (m, 211). 6.22 (m, 114), 5.91 (m.
11-1), 4.90 (m, 2H), 3.53 (m, 2H), 2.96 (m. 1H), 1.99 (in, 2H), 1.71 (m 1H), 1.55 (m, 1H) Example 208: Preparation of 6-fluoro-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylic acid dihydrochloride OH

The title compound (24 mg, yield: 81%) was obtained in the same manner as in Example 166, with the exception that 6-fluoro-11-1-indole-3-carboxylic acid was used instead of 5,6-dichloro-1H-benzo[d]imidazo1e in Step 166-5 of Example 166.
IH-NMR (500 MHz, Me0D): 6 7.99 (in, 2H), 7.15 (m, 1H), 6.95 (m, 114), 6.21 (m, 1H), 5.90 (m, 1H), 4.87 (in, 211), 3.60 (m, 11-1), 3.51 (in, 1H), 3.26 (in, III), 2.94 (in, IH), 2.01 (m, 2H), 1.71 (m, 1H), 1.56 (m, 1H) Example 209: Preparation of 1-0E)-34(2R,3S)-3-hydroxypiperidin-2-yDally1)-114-indole-3-carboxylic acid dihydrochloride OH
OH

The title compound (20 mg, yield: 78%) was obtained in the same manner as in Example 166, with the exception that 1H-indole-3-carboxylic acid was used instead of 5,6-dichloro-114-.
benzo[d]imidazole in Step 166-5 of Example 166.
H-NMR (500 MHz, Me0D): 5 8.05 (d, 114), 7.99 (d, IN), 7.45 (d, 1H), 7.16 (m, 214), 6.22 (in, 1H), 5.91 (in, 1H), 4.83 (m, 2H), 4.37 (m, I H), 3.61 (m, 1H), 3.52 (m, 1H), 2.94 (m, 1H), 2.00 (m, 2H), 1.69 (n, 1H), 1.53 (m, 11-1) Example 210: Preparation of methyl 4-chloro-14(E)-34(2R,3S)-3-hydroxypiperidin-2-yl)a11y1)-1H-indole-3-carboxylate dihydrochloride ----- CI

The title compound (18 mg, yield: 82%) was obtained in the same manner as in Example 166, with the exception that methyl 4-chloro-1H-indole-3-carboxylate was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
H-NMR (500 MHz, Me0D): 5 8.05 (s, 1H), 7.44 (d, 1H), 7.20 (m, 2H), 6.17 (m, 1H), 5.42 (n, 1H), 4.98 (in, 2H), 3.84 (s. 3H), 3.45 (m, 2H), 3.18 (n, 114), 2.89 (in, 1H), 1.94 (m, 2H), 1.64 (m, 114), 1.50 (n, 114) Example 211: Preparation of methyl 6-chloro-14(E)-34(2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylate dihydrochloride CI
The title compound (28 mg, yield: 80%) was obtained in the same manner as in Example 166, with the exception that methyl 6-chloro-1H-indole-3-carboxylate was used instead of 5,6-clichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
'11-NIViR (500 MHz, Me0D): 6 8.02 (m, 21-1), 7.56 (s, 1H), 7.22 (t, 11-1), 6.17 (m, 1H).
5.45 (m, IH), 4.96 (m, 2H), 3.87 (s, 3H), 3.46 (m, 2H), 3.20 (m, 1H), 2.89 (m, 1H), 1.95 (m, 2H), 1.65 (m, I H), 1.51 (m, 1H) Example 212: Preparation of methyl 7-chloro-14(E)-3-02R,.3S)-3-1 0 hydroxypiperidiuri-2-yDaLly1)-111-indole-3-carboxylate dihydrochloride The title compound (28 mg, yield: 84%) was obtained in the same manner as in Example 166, with the exception that methyl 7-chloro-1H-indole-3-carboxylate was used instead of 5,6-dichloro-1H-benzo[dlimidazote in Step 166-5 of Example 166.
'H-NMR (500 MHz, Me0D): 6 8.08 (d, 114), 8.03 (s, 1H, 7.25 (d, 1H), 7.16 (m, 1H), 6.26 (m, I H), 5.28 (m, 2H), 3.89 (s, 3H), 3.65 (s, 1H), 3.46 (m, 2H), 3.16 (m, 1H), 2.90 (in, 1H), 1.95 (m, 2H), 1.60 (m, 1H), 1.50 (in, 1H) Example 213: Preparation of methyl 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-1H-indole-3-carboxylate dihydrochloride Br The title compound (30 mg, yield: 85%) was obtained in the same manner as in Example 166, with the exception that methyl 5-bromo-1H-indole-3-carboxylate was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
H-NMR (500 MHz, Me0D): 6 8.19 (d, 111). 8.04 (d, 1H), 7.36 (m, 21-1), 6.17 (m, 1H), 5.46 (m, 1H), 4.97 (in, 2H), 3.90 (s, 3H), 3.43 (m, 2H), 3.20 (m, 1H), 2.88 (m, 1H), 1.97 (m, 2H), 1 .66 (m, 1H), I .51 (m, Ii-I) Example 214: Preparation of methyl 6-bromo-14(E)-34(2R93S)-3-hydroxypipericlin-2-yl)allyl)-1H-indole-3-carboxylate dihydrochloride Br The title compound (31 mg, yield: 83%) was obtained in the same manner as in Example 166, with the exception that methyl 6-bromo-1H-indole-3-carboxylate was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
IH-NMR (500 MHz, Me0D): 6 7.96 (m, 21-1), 7.71 (s, 114), 7.33 (m, 1H), 6.17 (m, 11-1).
5.44 (m, 11-1), 4.96 (m, 2H), 3.87 (s, 3H), 3.47 (m, 2H), 3.19 (m, 1H), 2.89 (m, I H), 1.97 (in, 2H), 1.65 (m, 11-1), 1.51 (in, 11-1) Example 215: Preparation of 5-bromo-1-0E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)ally1)-N-methyl-1H-indole-3-carboxamide dihydrochloride NH
Br The title compound (21 mg, yield: 86%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-N-methyl-1H-indole-3-carboxamide was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
I H-NMR (500 MHz. Me0D): 6 8.25 (m. 1H), 7.84 (s, 11-1), 7.34 (m, 2H), 6.16 (m, 11-E), 5.38 (in, 1H), 4.89 (m, 2H), 3.44 (in, 2H), 3. 16 (m, 1H), 2.86 (m, 4H), 1.94 (in, 2H), 1.63 (in, 1H), 1.48 (m, 1H) Example 216: Preparation of 5-bromo-14(E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyb-N,N-dimethyl-1H-indole-3-carboxatnide dihydrochloride 2HCI Br The title compound (21 mg, yield: 86%) was obtained in the same manner as in Example 166, with the exception that 5-bromo-N,N-dimethy1-1H-indole-3-carboxylamide was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1-1MR (500 MHz, Me0D): 6 7.95 (s, 1H), 7.71 (s, 114). 7.41 (d. 1H), 7.34 (m, 1H), 6.14 (in, 1H), 5.39 (m, 1H), 4.96 (in, 21-1), 3.45 (in, 2H), 3.16 (in, 7H), 2.89 (m, 1H), 1.97 (m, 2H), 1.65 (m, I H), 1.50 (in, 1H) Example 217: Preparation of (2R,3S)-24(Z)-3-(5-chloro-4-methyl-1H-benzo[djimidazol-1-y1)-2-fluoroprop-I-enyl)piperidin-3-ol dihydrochloride F N
CI

The title compound (25 mg, yield: 80%) was obtained in the same manner as in Example 166, with the exception that triethyl 2-fluoro-2-phosphonoacetate was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and 5-chloro-4-methy1-1H-benzo[d]imidazole was used instead of 5,6-dichloro-11-1-benzo[d]imidazole in Step 166-5 of Example 166.
1H-NMR (500 MHz, Me0D): 6 8.30 (s, 1). 7.52 (d, 111), 7.32 (d, 1H), 5.36 (m, 1H), 5.25 (m, 1H), 5.19 (m, 1H), 3.36 (t, IN), 3.31 (m, I H), 3.10 (d, IH), 2.79 (in, 1H), 2.61 (s, 3H), 2.15 (m, 1H), 1.87 (m, 1H), 1.68 (m, 1H), 1.56 (in, 1H) Example 218: Preparation of (2R,3S)-2-0Z)-3-(5-bromo-4-methyl-IH-2 5 benzofdlimidazol-1-y1)-2-fluoroprop-1-en-1-Apiperidin-3-ol dihydrochloride õ0$
2HCI -Br The title compound (27 mg, yield: 81%) was obtained in the same manner as in Example 166, with the exception that triethyl 2-fluoro-2-phosphonoacetate was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and 5-bromo-4-methyl-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
11-1-NMR (500 MI-lz, Me0D): 6 8.29 (s, 11-1), 7.46 (s, 2H), 5.35 (m, 1H), 5.25 (m, 1H), 5.21 (m, 1H), 3.54 (t, 1H), 3.41 (in, 1H), 3.12 (d, 1H), 2.77 (in, 1H), 2.63 (s, 3H), 2.15 (m, 1H), 1.87 (m, 1H), 1.68 (in, 114), 1.56 (m, 1H) Example 219: Preparation of (2R,3S)-2-0Z)-3-(5,6-dichloro-1H-benzoldlimidazol-1-y1)-2-fluoroprop-1-en-1-yOpiperidin-3-ol dihydrochloride CI

CI
The title compound (35 mg, yield: 84%) was obtained in the same manner as in Example 166, with the exception that triethyl 2-tluoro-2-phosphonoacctate was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166.
11-I-NMR (500 MHz, Me0D): 6 8.38 (s, 1H), 8.00 (s, 11-1), 7.80 (s, 1F-1), 5.26 (m, 3H), 3.59 (t, 1H), 3.42 (m, 1H), 3.14 (d, 1H), 2.83 (t, 1H), 2.14 (m, 11-1), 1.89 (d, 1H), 1.69 (m, 1H), 1.58 (m, 1H) Example 220: Preparation of (2R,3S)-24(Z)-345,6-dichloro-2-(hydroxymethyl)-1H-benzo[cliimidazol-1-y1)-2-fluoroprop-1-en-1-y1)piperidin-3-ol dihydrochloride OH
2,,OHF
CI
HCI
CI
The title compound (30 mg, yield: 79%) was obtained in the same manner as in Example 166, with the exception that triethyl 2-fluoro-2-phosphonoacetate was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and (5,6-dichloro-1H-benzo[d]imidazol-2-yOmethanol was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
'H-NMR (500 MHz, Me0D): 6 8.01 (s, 1H), 7.71 (s. 1H), 5.41 (in, 31-1), 4.85 (m, 3.80 (m, 11-1), 3.57 (m, 21-1), 3.26 (s, 1H), 2.96 (t, 1H), 2.18 (iii, 1H), 1.98 (m, I H), 1.73 (m, 1H), 1.63 (m, 1H) Example 221: Preparation of (211,3S)-24(E)-3-(5-chloro-4-methyl-1H-1 0 benzo[cliimidazol-1-y1)-2-methylprop-1-en-l-yppiperidin-3-ol dihydrochloride The title compound (27 mg, yield: 81%) was obtained in the same manner as in Example 166, with the exception that (1-ethoxycarbonylethylidene diene)triphenylphosphorane was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and 5-chloro-4-methyl-1H-benzo[d]imidazolc was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 166-5 of Example 166.
H-NMR (500 MHz, Me0D): 6 8.21 (s, 1H), 7.39 (d. Fr). 7.31 (d, 1H). 5.13 (d, 1H), 4.93 (m, 2H), 3.62 (t, 1H), 3.39 (m, 1H), 3.15 (m, 1H), 2.87 (m, 11-1), 2.62 (s, 3H), 2.06 (in, 11-1) 1.93 (m, 1H), 1.78 (s, 3H), 1.62 (m, 1H), 1.57 (m, 1H) Example 222: Preparation of (2R,3S)-2-((E)-3-(5-bromo-4-methyl-1H-benzof djimidazol-1-y1)-2-methylprop-1-en-l-y1)piperidin-3-ol dihydrochloride Br The title compound (34 mg, yield: 80%) was obtained in the same manner as in Example 166, with the exception that (1-ethoxycarbonylethylidene diene)tnphenylphosphorane was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and 5-bromo-4-methy1-1H-benzo[djimidazole was used instead of 5,6-d ichloro-1H-benzo[d]im idazole in Step 166-5 of Example 166.
1H-NfMR (500 MHz. Me0D): 68.20 (s, 1H), 7.47 (d. 114), 7.35 (d, 1H), 5.12 (d, 1H), 4.93 (m, 2E1), 3.62 (t, I FI), 3.40 (in, 1H), 3.15 (n), 1H), 2.86 (m, 1f1), 2.64 (s, 31-1), 2.06 (m, 1H), 1.92 (m, 1H), 1.78 (s, 31-1), 1.66 (m, IH), 1.56 (m, 1H) Example 223: Preparation of (2R,3S)-2-((E)-3-(5,6-dichloro-1H-benzoldlimidazol-1-yl)-2-methylprop-1-en-1-yl)piperidin-3-ol dihydrochloride CI

CI
The title compound (28 mg, yield: 78%) was obtained in the same manner as in Example 166, with the exception that (1 -ethoxycarbonylethylidene)triphenylphosphorane was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166.
IFI-NMR (500 MHz, Me0D): 6 8,28 (s, 1E1), 7.83 (s, 2H), 5.18 (d, IH), 4.91 (m, 2H), 3,48 (t, IH), 3.07 (d, 1H), 2.76 (t, 1H), 2.07 (m, 11-1), 1.86 (in, 114), 1.76 (s, 3H), 1.62 (in, 1H), 1.46(m, 1H) Example 224: Preparation of (2R,3S)-24(E)-3-(5,6-dich1oro-2-(hydroxymethyl)-1H-benzoldlimidazol-1-yl)-2-methylprop-1-en-l-yl)piperidin-3-ol dihydrochloride OH
N
N
CI

CI
The title compound (31 mg, yield: 78%) was obtained in the same manner as in Example 166, with the exception that (1-ethoxycarbonylethylidene)triphenylphosphorane was used instead of (carbethoxymethylene)triphenylphosphorane in Step 166-1 of Example 166, and 5,6-dichloro-I H-benzo[d]imidazol-2-yl)methanol was used instead of 5,6-dichloro-1H-benzo[d]imidazo1e in Step 166-5 of Example 166.
1H-NMR (500 MHz. Me0D): 67.79 (s, 5.03 (in, 2H), 4.89 (in, 3H), 3.70 (1, 1H), 3.40 (in, 1H), 3.14 (in, 1H), 2.92 (in, 1H), 2.03 (m, 1H), 1.94 (in, 111), 1.84 (s, 3E1), 1.65 (in, 1H), i 31 1.55 (m, 1H) Example 225: Preparation of (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)piperidin-3-ol dihydrochloride CI
Step 225-1: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(E)-3-ethoxy-3-oxoprop-1-en-l-yl)piperidine-1-carboxylate Methylene chloride (47 mL, 0.12 N4) and oxalyl chloride (1.0 mL, 11.6 mmol) were added to a flask filled with nitrogen and the reaction solution was cooled to -78 C.
Dimethylsulfoxide (1.7 mL, 23.2 mmol) was then added at the same temperature and stirred for 30 minutes. Then, tert-butyl = ________________________ (2R,3 S)-3-((tei t-butyldimethylsilyl)oxy)-2-(hydroxymethyl)piperidine-1 -carboxylate (2.0 g, 5.8 mmol) was dissolved in a small amount of methylene chloride and slowly added. After stirring at the same temperature for 1 hour, triethylamine (3.3 mL, 23.2 mmol) was added and the temperature of the reaction solution was raised to room temperature from -78 C. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected and dried with magnesium sulfate, filtered and concentrated under reduced pressure, and then dissolved in methylene chloride (47 mL, 0.12 M), and (carbethoxymethylene)triphenylphosphorane (4.0 g, 11.6 mmol) was added thereto at room temperature and stirred for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and and pun i tied by column chromatography (hexane:
ethyl acetate = 4:1) to give the title compound (2.1 g, 89% yield over two steps).
Step 225-2: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-ethoxy-3-oxoprop-1-yn- I -yl)piperidine-l-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(E)-3-ethoxy-3-oxoprop-1-en-l-y1)piperidine- 1 -earboxylate (3.2 g, 7.7 mmol) obtained from Step 225-1 was dissolved in methanol (50 mL, 0.15 M), and a lindlar catalyst (82 mg, 0.77 mmol) was added thereto. After connecting a hydrogen balloon, the mixture was stirred at room temperature for 5 hours. When the reaction was completed, the reaction solution was filtered through celite and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 225-3: Preparation of 3-((2R,3S)-1-(tert-butoxycarbony1)-3-(tert-butyldimethylsilyl)oxy)pipendin. -2-yl)propenoic acid Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-ethoxy-3-oxoprop-1-yn-1-yl)piperidine- 1 -carboxylate (3.0 g, 7.2 mmol) obtained from Step 225-2 was dissolved in methanol (20 mL, 0,36 M), and then 2N aqueous sodium hydroxide solution (10 mL) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction solution was neutralized with IN aqueous hydrochloric acid solution, acidified, diluted with ethyl acetate and then washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 225-4: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(3-hydroxyprop-1-yn-l-y1)piperidine- I -carboxylate 3-((2R,3S)-1-(tert-butoxycarbony1)-3-(tert-butyldimethylsilyl)oxy)piperidin-2-y1)propenoic acid (1.6 g, 4.0 mmol) obtained from Step 225-3 was dissolved in tetrahydrofuran (50 mL, 0.08 M), and the reaction solution was cooled to 0 C. Then, a lithium aluminum hydride solution (1.6 mL, 4.0 mmol) was slowly added thereto, reacted at the same temperature for 30 minutes and then stirred at room temperature for 2 hours. A small amount of water was added to complete the reaction, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (dichloromethane:
methanol = 10:1) to give the title compound (1.3 g, yield: 85%).

Step 225-5: Preparation of ten-butyl (2R,3S)-2-(3-bromoprop-1-yn- I -yl)-3-((tert-butyldimethylsilypoxy)piperidine-l-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-hydroxyprop-1-yn-l-yl)piperidine- 1 -carboxylate (100 mg, 0.27 mmol) obtained from Step 225-4 was added to methylene chloride (100 mL, 0Ø3 M). The reaction solution was cooled to 0 C, and then triphenylphosphine (107 g, 0.41 mniol) and tetrabromomethane (135 g, 0.41 mmol) were sequentially added at the same temperature, followed by stirring at room temperature for 2 hours.
When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 5:1) to give the title compound (89 g, yield: 76%).
Step 225-6: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-(3-(5,6-1 5 dichloro-1H-benzo[d]imidazol-1-y1)prop-1-yn-1-y1)piperidine-1-carboxylate Tert-butyl (2R,3S)-2-(3-bromoprop-1-yn-l-y))-3-((tert-butyldimethylsilypoxy)piperidine- 1 -au-boxylate (200 mg, 0.46 mmol) obtained from Step 225-5 was dissolved in N,N-dimethylformamide (5 mL, 0.69 M). Then, potassium carbonate (127 mg, 0.92 mmol) and 5,6-dichloro-1FI-benzo[d]inaidazole (86 mg, 0.46 mmol) were added thereto, and the mixture was stirred at room temperature for 4 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 1:2) to give the title compound (293 mg, yield 85%).
Step 225-7: Preparation of (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-yn-1-y1)piperidin-3-ol dihydrochloride Tert-butyl (2R,3S)-3-((tert-butyldimethylsitypoxy)-2-(3-(5,6-diehloro-1H-benzo[d]imidazol-1-y1)prop- I -yn-l-yl)piperidine-1-carboxylate (293 mg, 0.54 mmol) obtained from Step 225-6 was dissolved in a small amount of tetrahydrofuran and 4N
hydrogen chloride dioxane solution (5 mL, 0.10 M) was added thereto, and the mixture was heated and stirred at room temperature for 12 hours. When the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved by addition of a small amount of methanol and then crystallized with diethyl ether to give the title compound (176 mg, yield: 82%).
1H-NMR (500 MHz, Me0D): 6 8.44 (br, 114), 7.99 (s, 11-0, 7.88 (s, IF-I), 5.34 (s, 2H), 4.11 (m, 1H), 3.90 (m, 1H), 3.22 (m, 1H), 3.04 (m, 1H), 1.99 (m, 2H), 1.65 (m, 2H) Example 226: Preparation of (2R,.3S)-2-(3-(5-hromo-4-methy1-1H-benzordlimidazol-1-yl)prop-1-yri-i-yl)piperidin-3-ol dihydrochloride õOH
r-r_N
N /
H N
2HCI Br The title compound (42 mg, yield: 85%) was obtained in the same manner as in Example 225, with the exception that 5-bromo-4-methyl-11-1-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]im idazole in Step 225-6 of Example 225.
H-NMR (500 MHz, Me0D): 6 9.61 (m, 1H), 7.86 (in, 1I-f), 7.78 (m, 111), 5.57 (d, 2H).
4.86 (m, 1H), 4.16 (m, 1H), 3.97 (m, 1H), 3.06 (in, 1H), 2.72 (s, 31-1), 2.02 (m, 21-1), 1.65 (ni, 2H) Example 227: Preparation of (2R,3S)-2-(3-(5-chloro-4-methyl-1H-benzoldlimidazol-1-y1)prop-1-yn-1-yl)piperidin-3-ol dihydrochloride The title compound (35 mg, yield: 81%) was obtained in the same manner as in Example 225, with the exception that 5-chloro-4-methyl-1H-benzokl]imidazole was used instead of 5,6-dichloro-1H-benzo[d]im idazole in Step 225-6 of Example 225.
1H-NMR (500 MHz. Me0D): 6 9.65 (s, 11-), 7.86 (d, If-I). 7.71 (d, 11-1), 5.57 (s, 2H), 4.82 (in, 1H), 4.16 (m, I H), 3.95 (in, 1H), 3.05 (m, 1H), 2.17 (s, 3H), 2.00 (m, 21-1), 1.63 (in, 2H) Example 228: Preparation of (2R,3S)-2-(3-(5,6-dibromo-1H-benzordlimidazol-1-yl)prop-1-yn-1-yl)piperidin-3-ol dihydrochloride 2HCI Br Br The title compound (30 mg, yield: 80%) was obtained in the same manner as in Example 225, with the exception that 5,6-dibromo-IH-benzo[d.limidazole was used instead of 5,6-dichloro-1H-benzo[d]imidazole in Step 225-6 of Example 225.
I H-NMR (500 MHz, Me0D): 6 9.18 (br, 1H), 8.39 (s, 1H), 8.20 (m, 1H), 5.47 (s, 2H), 4.88 (in, 1H), 4.16 (m, 1H), 3.94 (m, 1H), 3.06 (in, 1H), 1.99 (m, 21-1), 1.68 (m, 2H) Example 229: Preparation of (2R,.3S)-2-(3-(5-fluoro-4-methy1-1H-benzoldlimidazol-1-yl)prop-1-yn-1-yl)piperidin-3-ol dihydrochloride The title compound (28 mg. yield: 75%) was obtained in the same manner as in Example 225, with the exception that 5-fluoro-4-methyl-1H-benzo[d]imidazole was used instead of 5,6-dichloro-1H-benzo[d]irnidazole in Step 225-6 of Example 225.
H-NMR (500 MHz. Me0D): 6 8.44 (br, 1H). 7.99 (s, 11-1), 7.88 (s, 11-1), 5.34 (s, 214), 4.11 (in, IH), 3.90 (m, 1H), 3.22 (m, 1H), 3.04 (m, 1H), 1.99 (m, 2H), 1.65 (m, 2H) Example 230: Preparation of (2R,.3S)-24(E)-3-(5,6-dichloro-1H-benzoldjimidazol-2 0 1-yl)prop-1-en-l-yl)pyrrolidin-3-ol dihydrochloride õOH
N \

CI
Step 230-1: Preparation of (2 R,3 S)- I -(tert-butoxycarbony1)-3-((tert-butyldimethylsilyl)oxy)pynolidine-2-carboxylic acid (2R,3S)-1-(tert-butoxycarbony1)-3-hydroxypyriplidine-2-carboxylic acid (10.7 g, 46.2 mmol) was dissolved in N,N-dimethylformamide (100 mL, 0.46 M). Then, the reaction solution was cooled to 0 C, and tert-butyldimethylsilyl chloride (20.9 g, 138.6 mmol) and triethylamine (32.2 mL, 231.0 mmol) were added thereto. The reaction solution was stirred at room temperature for 12 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (dichloromethane:
methanol = 7:
1) to give the title compound (14.4 g, yield: 90%).
Step 230-2: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-(hydroxymethyl)pyiTolidine- I -carboxylate (2 R,3S)-1-(tert-butoxycarbonyI)-3 -((tert-butyld imethylsi lyl)oxy)pyrrol idine-2-ca rboxyli c acid (2.0 g, 4.3 mmol) obtained from Step 230-1 was dissolved in tetrahydrofuran (50 mL, 0.09 is M).
Then, the reaction solution was cooled to 0 C and a borane solution (5.2 mL, 4.7 rnmol) was added thereto. The reaction solution was stirred at the same temperature for 1 hour and then stirred at room temperature for 2 hours. A small amount of methanol was added to complete the reaction.
Mier removing the solvent, the reaction solution was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected and the resulting mixture was dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 3:1) to give the title compound (1.1 g, yield 80%).
Step 230-3: Preparation of tert-butyl (2R,35)-3-((tert-butyldimethylsilyl)oxy)-24(E)-3-2 5 ethoxy-3-oxoprop- I -en- I -3/1)pyrrol idine-l-carboxyl ate Methylene chloride (61 mL, 0.12 M) and oxaly1 chloride (0.76 mL, 8.7 mmol) were added to a flask filled with nitrogen and the reaction solution was cooled to -78 C. N,N-dimethylsulfoxide (1.2 mL, 17.4 mmol) was then added at the same temperature and stirred for 30 minutes. Then, tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-(hydroxymethyl)pyrrolidine-3 0 l -carboxylate (1.4 g, 4.3 mmol) obtained from Step 230-2 was dissolved in a small amount of methylene chloride and slowly added. After stirring at the same temperature for 1 hour, triethylamine (2.4 mL, 17.4 rrunol) was added and the temperature of the reaction solution was raised to room temperature from -78 C. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried with magnesium sulfate, filtered and concentrated under reduced pressure, and then dissolved in methylene chloride (20 mL, 0.22 M), and (carbethoxymethylene)triphenylphosphorane (3.0 g, 8.7 mmol) was added thereto at room temperature and stirred for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane:
ethyl acetate = 4:1) to give the title compound (1.5 g, yield: 87%).
Step 230-4: Preparation of (E)-3 -((2R,3 S)-1 -(tert-butoxycarbony1)-3-((tert-1 5 butyldimethylsilypoxy)pyrrolidin-2-ypacrylic acid Tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-2-((E)-3-ethoxy-3-oxoprop-1-en- 1-yl)pyrrolidine-l-carboxylate (1.5 g, 3.8 mmol) obtained from Step 230-3 was dissolved in ethanol (27 inL, 0.14 M), and then 2N aqueous sodium hydroxide solution (8 mL) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction solution was neutralized with IN aqueous hydrochloric acid solution, acidified and then diluted with ethyl acetate, and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Subsequent reactions were carried out without purification procedure.
Step 230-5: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilypoxy)-24(E)-3-hydroxyprop-1-en-1-y1)pyrrolidin-l-carboxylate (E)-3-((2R,3S)-1-(tert-butoxycarbony1)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)aciylic acid (400 mg, 1.1 mmol) obtained from Step 230-4 was dissolved in tetrahydrofuran (10 mL, 0.1 M), and the reaction solution was cooled to 0 C. Then, a lithium aluminum hydride solution (0.43 mL, 1.1 mmol) was slowly added thereto, reacted at the same temperature for 30 minutes and then stirred at room temperature for 2 hours. A small amount of water was added to complete the reaction, diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (dichloromethane:
methanol = 10:1) to give the title compound (328 g, yield: 85%).
Step 230-6: Preparation of tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-24(E)-3-(5,6-dichloro-IH-benzo[dlimidazol-1-y1)prop-1-en-l-yl)pyrrolidine-1-carboxylate Tert-butyl (2R,3S)-3-((tert-butyldimethylsilyl)oxy)-2-((E)-3-hydroxyprop-1-en-1-yl)pyrrolidin- 1 -carboxylate (177 mg, 0.49 mmol) obtained from Step 230-5 was added to methylene chloride (5 mL, 0.1 M). The reaction solution was cooled to 0 C, and then a 50%
aqueous solution of potassium hydroxide (0.05 mL, 0.49 mmol) and para-toluenesulfonyl chloride (104 mg, 0.55 mmol) were sequentially added at the same temperature, followed by stirring at room temperature for 2 hours. When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected and dried over magnesium sulfate, filtered and then concentrated under reduced pressure, and dissolved in N,N-dimethylfomiarnide (3 mL, 0.16 M).
Then, potassium carbonate (53 mg, 0.38 mmol) and 5,6-clichloro-1H-benzo[d]imidazole (92 mg.
0.49 mmol) were added thereto and stirred at room temperature for 4 hours.
When the reaction was completed, the solvent was removed, and the resulting mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure, and then purified by column chromatography (hexane: ethyl acetate = 1:1) to give the title compound (155 mg, yield: 60%).
Step 230-7: Preparation of (2R,3S)-2-((E)-3-(5,6-dichloro- 1H-benzo[d]imidazol-y1)prop-1-en-1-y1)pyrrolidin-3-ol dihydrochloride Tert-butyl (2 R,3S )-3-((tert-butyld imethylsi lyl)oxy)-2-((E)-3-(5,6-di chloro-1H-benzo[d]imidazol- I -yl)prop- 1 -en-l-yl)pyrrol idine-l-carboxylate (43 mg, 0.08 mmol) obtained from Step 230-6 was dissolved in a small amount of tetrahydrofuran and then a 4N hydrogen chloride dioxane solution (2 mL, 0.04M) was added thereto and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, dissolved by addition of a small amount of methanol, and then crystallized with diethyl ether to give the title compound (25 mg, yield 79%).
I H-NMR (500 MHz, DMS0-4: 5 8.80 (s. IN), 8.11 (s, 1H), 8.04 (s, IN), 6.12 (m, 1H), 5.78 (m, 1H), 5.02 (d, 21-1), 4.05 (m, 1H), 3.81 (m, I H), 3.22 (m, 2H), 2.10 (m, 1H), 1.79 (m, 1H) Experimental Example: PRS enzyme activity inhibition experiment In order to confirm the biological activities of the compounds prepared in Examples, %inhibition or IC50 values of PRS enzyme (phosphoribosylpyrophosphate synthetase enzyme) activities were calculated.
Specifically, the portion corresponding to PRS in cDNA of EPRS was subclonmi, and the obtained high-purity PRS protein was purified and used in the experiment.
The compounds (1 iLtM) prepared in Examples were added into the reaction buffer (20 mM KPO4 (pH
7.4), 6 mM
MgAc, 5 mM ATP, 400 tRNA, 0.5 mM DTT, 20 mCi[3H]proline (1 mCiimL)) and allowed to react at 37 C for 5 to 10 minutes. The reaction was terminated with 3M paper that was in advance dried by addition of 5% TCA. The radioactivity was measured using a liquid scintillation counter.
% Inhibition and IC50 values of the respective compounds were calculated and analyzed using Microsoft Excel or Sigma Plot 8Ø The results are shown in Tables 1 to 3 below. In Tables 1 to 3, the results are divided into A, B and C according to the range of IC50. The case where the derived IC50 is 100 riM or less is represented by "A", the case where the 1050 is 100 to 500nM is represented by "B", and the case where the IC50 is 500 nM or higher is represented by "C".
[Table 1]
Example Example Example Example PRS IC

No. No. No. No.

9 C 29 C 49 B 69 . A
-11 B 31 B . 51 C 71 B
12 B 3" B 52 B 72 B
13 C _ 33 B 53 B 73 B

B . 35 B 55 C 75 C
16 B _ 36 B 56 B 76 C
17 C 37 B 57 C 77 , B
18 . C 38 C 58 A 78 B

[Table 2]
Example Example Example Example PRS IC PRS ICso PRS IC50 PRS ICso No. No. No. No 81 C 101 A 121 . B 141 C , ¨
82 _ C 102 B 122 B 14" C

85 B 105 C 125 C , 145 C

87 B 107 B 127 . B 147 C

_ 91 A 111 A 131 B 151 . B
. 92 B 112 B 132 B 152 C
93 C 113 B 133 C 153 . B

95 . B 115 B 135 C 155 C
_ 97 A 117 B . 137 C 157 , C

99 A 119 C . 139 C 159 C

[Table 3]
Example Example Example Example PRS !Co PRS 1C5n PRS 1050 PRS fC50 No. No. No. No.

163 C 183 B 203 C 223 . C

_ 165 C . 185 C 205 C 225 C
166 B 186 B . 206 C 226 C

169 C 189 B 209 C _ 229 C

170 B ' 190 B 210 C 230 C
171 C 191 B 211 , C

_ 177 C 197 C 217 C ,

Claims (15)

    WHAT IS CLAIMED IS:
  1. [Claim 1]
    A compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
    in Chemical Formula I, n is 1, or 2, L is -CH2CH2-, -CH=C(R')-, or -C.ident.C-, wherein R' is hydrogen. C1-4 alkyl, or halogen, X1 is CR1R2, NR1, or -CO-, X2 is CR3R4, or NR3, wherein R1 to R4 are each independently hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, hydroxy, amino, carboxy, -COO(C1-4 alkyl), -CONH2, -CONH(C1-4 alkyl), -CON (C1-4 alkyl)2, or pyrazolyl unsubstituted or substituted with C1-4 haloalkyl; or R1 and R3, together with each other, links X1 and X2 via a double bond, and A is benzene, pyridine, pyrimidine, or pyrimidinedione ring, wherein A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of a ring-type substituent selected from the gimp consisting of furanyl, imidazolyl, isoxazolyl, phenyl, pyrazolyl, pyridinonyl, pyridinyl, pyrrolyl, thiazolyl, and thiophenyl; C1-4 alkyl; C1-4 alkoxy; C1-4 haloalkyl;
    C1-4 haloalkoxy; halogen;
    di(C1-4 alkyl)amino; nitro; -COO(C1-4 alkyl); dihydropyranyl; rnorpholino;
    piperidinyl; and pyrrolidinyl; and wherein the ring-type substituent is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C1-5 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, monovalent of C2-5 alkylene carbonate, -COO(C1-4 alkyl), halogen, cyano, thiazolyl, and (1,3-dioxolan-2-yl)methyl.
  2. [Claim 2]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of C1-4 alkyl; C1-4 alkoxy;
    C1-4 haloalkyl;
    halogen; phenyl unsubstituted or substituted with halogen, or C1-4 haloalkyl;
    pyrazolyl unsubstitued or substituted with C1-5 alkyl, thiazolyl, or C1-4 haloalkyl;
    thiopheny unsubstituted or substituted with C1-5 alkyl, or -COO(C1-4 alkyl); pyrrolyl unsubstituted or substituted with Ci-5 alkyl and/or -COO(C1-4 alkyl); di(C1-4 alkyl)amino; morpholino; piperidinyl, furanyl; and pyrrolidinyl.
  3. [Claim 3]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is -CH2CH2-, -CH¨CH-, -CH¨CF-, -CH=C(CH3)-, or -C.ident.C-.
  4. [Claim 4]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Chemical Formula I is represented by the following Chemical Formulas 1-1 to 1 -5*
    in Chemical Formulas 1-1 to 1-5, n, L, R1 to R4 and A are as defined in claim 1.
  5. [Claim 5]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 to R4 are each independently hydrogen, methyl, hydroxymethyl, hydroxy, ammo, carboxy, -COOCH3, -CONH2, -CONHCH3, or -CON(CH3)2: or R1 and R3, together with each other, link X1 and X2 via a double bond.
  6. [Claim 6]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is benzene, pyridine, pyrimidine, or pyrimidinedione ring, and A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of methyl, isobutyl, methoxy, trifluoromethyl, fluoro, chloro, bromo, phenyl, phenyl substituted with fluoro, phenyl substituted with chloro, phenyl substituted with trifluoromethyl, thiophenyl, thiopheny substituted with methyl, thiopheny substituted with -COOCH1, pyrazolyl substituted with difluoromethyl, pyrazolyl substituted with methyl, pyrazolyl substituted with thiazolyl, pyrrolyl substituted with methyl and -COOCH2CH1, furanyl, dimethylamino, diethylamino, methylethylamino, morpholino, piperidinyl, and pyrrolidinyl
  7. [Claim 7]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is benzene, and A is unsubstituted or substituted with one to three substituents each independently selected from the group consisting of C1-4 alkyl; C1-4 alkoxy; halogen; and phenyl unsubstituted or substituted with halogen or C1-4 haloalkyl.
  8. [Claim 8]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is pyridine, and A is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy; halogen, and phenyl substituted with halogen
  9. [Claim 9]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is pyrimidine, and A is substituted with a substituent selected from the group consisting of halogen;
    alkyl)amino, morpholino, pipendinyl; and pyrrolidinyl
  10. [Claim 10]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A is pyrimidinedione, and A is unsubstituted or substituted with one or two C1-4 alkyl.
  11. [Claim 11]
    The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound represented by Chemical Formula 1 is selected from the group consisting of:
    1) (2R,3S)-2-(3-(6-chloro-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 2) (2R,3S)-2-(3-(4-bromo-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 3) (2R,3S)-2-(3-(5-bromo-1H-benzo[d]imidazol- -yl)propyl)piperidin-3-ol, 4) (2R,3S)-2-(3-(6-bromo-1H-benzo[d]imidazol- -yl)propyl)piperidin-3-ol, 5) (2R,3S)-2-(3-(7-bromo-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 6) (2R,3S)-2-(3-(4-fluoro-1H-benzo[d]imidazol- -yl)propyl)piperidin-3-ol, 7) (2 R,3S)-2-(3-(5-fluoro-1 H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 8) (2R,3S)-2-(3-(6-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 9) (2R,3S)-2-(3-(7-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 10) (2R,3S)-2-(3-(4-chloro-1H-benzo[d]imidazol-1-yl)propyppiperidin-3-ol, 11) (2R,3S)-2-(3-(5-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 12) (2R,3S)-2-(3-(7-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 13) (2R,3S)-2-(3-(6-methyl-1 H-benzo[d] imidazol-1-yl)propyl)piperidin-3-ol, 14) (2R,3S)-2-(3-(5-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 15) (2R,3S)-2-(3-(6-( trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 16) (2R,3S)-2-(3-(7-(trifluoromethyl)-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 17) (2R,3S)-2-(3-(7-(trifluoromethoxy)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 18) (2R,3S)-2-(3-(4-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 19) (2R,3S)-2-(3-(4-(piperidin- 1 -yl)- l H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 20) (2R,3S)-2-(3-(4-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 21) (2 R,3S)-2-(3-(4-(3-chlorophenyl )-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 22) (2R,3S)-2-(3-(5-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 23) (2R,3S)-2-(3-(6-(2-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 24) (2R,3S)-2-(3-(6-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 25) (2R,3S)-2-(3-(6-(4-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 26) (2R,3S)-2-(3-(7-(2-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 27) (2R,3S)-2-(3-(7-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 28) (2R,3S)-2-(3-(7-(4-fluorophenyl)-11-1-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 29) (2R,3S)-2-(3-(5-(1 H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 30) (2R,3S)-2-(3-(6-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 31) (2R,3S)-2-(3-(7-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 32) (2R,3S)-2-(3-(6-chloro-5-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 33) (2R,3S)-2-(3-(6-bromo-5-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 34) (2R,3S)-2-(3-(5-chloro-6-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 35) (2R,3S)-2-(3-(5-bromo-6-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 36) (2R,3S)-2-(3-(6-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 37) (2R,3S)-2-(3-(6-chloro-5-methoxy-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 38) (2R,3S)-2-(3-(6-fluoro-5-methoxy-1H-benzo[cl]imidazol-1-yl)propyl)piperidin-3-ol, 39) (2R,3S)-2-(3-(5-fluoro-6-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 40) (2R,3S)-2-(3-(4.5-dichloro-1 H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 41) (2S,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 42) (2S,3R)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 43) (2R,3R)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 44) (2R,3S)-2-(3-(4-chloro-5-methyl-11-1-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 45) (2R,3S)-2-(3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 46) (2R,3S)-2-(3-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 47) (2R,3S)-2-(3-(5-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 48) (2R,3S)-2-(3-(6-bromo-7-fluoro-1 H-benzo[d] imidazol-1-yl)propyl)piperidin-3-ol, 49) (2R,3S)-2-(3-(4,5-difluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 50) (2R,3S)-2-(3-(6,7-difluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 51) (2R,3S)-2-(3-(4,5-dimethyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 52) (2R,3S)-2-(3-(5,6-difluoro-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 53) (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 54) (2R,3S)-2-(3-(5,6-dibromo-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 55) (2R,3S)-2-(3-(5,6-dimethyl-1H-benzo[d]imidazol 1-yl)propyl)piperidin-3-ol, 56) (2R,3S)-2-(3-(6,7-dichloro-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 57) (2R,3S)-2-(3-(4,6-di fluoro-1H-benzo[d]imidazol- -yl)propyl)piperidin-3-ol, 58) (2R,35)-2-(3-(5,7-difluoro-1H-benzo[d]imidazol- -yl)propyl)piperidin-3-ol, 59) (2R,3S)-2-(3-(4-chloro-5-methoxy- 1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 60) (2R,3S)-2-(3-(7-chloro-6-methoxy- 1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 61) (2R,3S)-2-(3-(6-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 62) (2R,3S)-2-(3-(4-chloro-5-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 63) (2R,3S)-2-(3-(6-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 64) (2R,3S)-2-(3-(5-fluoro-4-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 65) (2 R,3S)-2-(3-(6- fluoro-7-methyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 66) (2R,3S)-2-(3-(4-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 67) (2 R,3S)-2-(3-(7-chloro-6-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 68) methyl 7-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazole-5-carboxylate, 69) (2 R,3S)-2-(3-(7-bromo-5-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 70) (2 R,3S)-2-(3-(5-bromo-7-chloro-1 H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 71) (2 R,3S)-2-(3-(7-bromo-5-(trifluoromethyl)-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 72) (2R,3S)-2-(3-(6-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 73) (2R,3S)-2-(3-(5-bromo-7-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 74) (2R,3S )-2-(3-(7-chloro-4-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-75) (2 R,3S)-2-(3-(5-bromo-4-nitro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 76) (2 R,3S)-2-(3-(6-bromo-7-nitro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 77) (2R,3S)-2-(3-(4-chloro-5-nitro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 78) (2R,3S)-2-(3-(7-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 79) (2R,3S)-2-(3-(5-chloro-7-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 80) (2R,3S)-2-(3-(5,7-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 81) (2R,3S)-2-(3-(5-chloro-7-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 82) (2R,3S )-2-(3-(7-(1H-pyrazol-4-yl)-5-(trifluoromethyl)-1 H-benzo[d]
    imidazol-1-yl)propyl)piperidin-3-ol, 83) (2R,3S)-2-(3-(5-chloro-7-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 84) (2R,3S)-2-(3-(7-(3-fluorophenyl)-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)propyl)pipenridin-3-ol, 85) (2R,3S )-2-(3-(5-chloro-7-(2-methylthiazol-5-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 86) (2R,3S)-2-(3-(5-chloro-7-(pyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 87) (2R,3S )-2-(3-(5-chloro-7-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 88) 5-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-7-yl)-1-methylpyridin-2(1H)-one, 89) (2R,3S)-2-(3-(5-chloro-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 90) (2R,3S)-2-(3-(5-chloro-7-(isoxazol-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 91) (2R3S)-2-(3-(5-chloro-7-(thiophen-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 92) (2R,3S)-2-(3-(5-chloro-7-(2-methylthiophen-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 93) (2R,3S)-2-(3-(5-chloro-7-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 94) (2R,3S)-2-(3-(5-chloro-7-(3,6-dihydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 95) (2R,3S)-2-(3-(7-(1((1,3-dioxolan-2-yl)methyl)-1H-pyrazol-4-yl)-5-chloro-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 96) (2R,3S)-2-(3-(5-chloro-7-(1-methyl-1H-imidazol-5-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 97) (2R,3S)-2-(3-(5-chloro-7-(1-methyl-1H-1-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 98) (2R,35)-2-(3-(7-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 99) (2 R,3S)-2-(3-(5-chloro-7-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 100) (2R,3S)-2-(3-(5-chloro-7-(2-cyclopropylthiazol-5-yl)-1H-benzo[d]imidazol-yl)propyl)piperidin-3-ol, 101) (2R,3S)-2-(3-(5-chloro-7-(1-(thiazol-2-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 102) (2R,3S)-2-(3-(5-chloro-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 103) (2R,3S)-2-(3-(5-chloro-7-(2-(tetrahydro-2H-pyran-4-yl)thiazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 104) (2R,3S)-2-(3-(5-chloro-7-(furan-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 105) 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-7-yl)thiazole-2-carbonitrile, 106) (2R,3S)-2-(3-(7-( I -(tert-butyl)- l H-pyrazol-4-yl)-5-chloro-IH-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 107) (2R,3S)-2-(3-(5-chloro-7-(1-isopentyl-1H-pyrazol-4-yl)- 11-1-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 108) (2R,3S)-2-(3-(5-chloro-7-(1-isopropyl-11-1-pyrazol-4-yl)- I H-benzo[d]imidazol- I -yl)propyl)piperidin-3-ol, 109) (2R,3S)-2-(3-(5-chloro-7-(4-methylthiophen-3-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 110) ethyl 3-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-7-yl)furan-2-carboxylate, 111) methyl 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-7-yl)thiophene-2-carboxylate, 112) (2R,3S)-2-(3-(5-chloro-7-( 1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 113) (2R,3S)-2-(3-(7-(1-butyl-1H-pyrazol-4-yl)-5-chloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 114) (2R,3S)-2-(3-(5-chloro-7-(2,5-dimethylthiophen-3-yl)-1H-benzo[d]imidazol-yl)propyl)piperidin-3-ol, 115) (2R,3S)-2-(3-(5-chloro-7-(1-isobutyl-1 H-pyrazol-4-yl)-1H-benzo[d]imidazol- 1 -yl)propyl)piperidin-3-ol, 116) ethyl 4-(5-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)- 1H-benzo[d]imidazol-7-yl)-1-methyl-1H-pyrrole-2-carboxylate, 117) (2 R,3S)-2-(3-(5-chloro-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 118) (2R,3S)-2-(3-(5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 119) (2 R,3S)-2-(3-(5-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 120) (2R,3S)-2-(3-(6-bromo-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 121) (2R,3S)-2-(3-(5-methyl-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 122) (2R,3S)-2-(3-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)propyl)piperidin-3-ol.
    123) (2R,3S)-2-(3-(6-chloro-3H-imidazo[4,5-c]pyridin-3-yl)propyl)piperidin-3-ol, 124) (2R,3S)-2-(3-(6-bromo- 1H-imidazo[4,5-c]pyridin-1-yl)propyl)piperidin-3-ol, 125) (2R,3S)-2-(3-(6-bromo-3H-imidazo[4,5-c]pyridin-3-yl)propyl)piperidin-3-ol, 126) (2R,3S)-2-(3-(7-chloro-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 127) (2R,3S)-2-(3-(5,6-dichloro-1H-imidazo[4,5-b]pyridin-1-yl)propyl)piperidin-3-ol, 128) (2R,3S)-2-(3-(7-bromo-1H-imidazo[4,5-c]pyridin-1-yl)propyl)piperidin-3-ol, 129) (2R,3S)-2-(3-(5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 130) (2R,3S)-2-(3-(6,7-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 131) (2R,3S)-2-(3-(6-chloro-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 132) (2R,3S)-2-(3-(6-bromo-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 133) (2R,3S)-2-(3-(6-bromo-7-chloro-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 134) (2R,3S)-2-(3-(7-chloro-6-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl)propyl)piperidin-3-ol, 135) (2R,3S)-2-(3-(2-chloro-7H-purin-7-yl)propyl)piperidin-3-ol, 136) (2R,3S)-2-(3-(2-chloro-9H-purin-9-yl)propyl)piperidin-3-ol, 137) (2R,3S)-2-(3-(6-(dimethylamino)-9H-purin-9-yl)propyl)piperidin-3-ol, 138) (2R,3S)-2-(3-(6-(diethylamino)-9H-purin-9-yl)propyl)piperidin-3-ol, 139) (2R,3S)-2-(3-(6-(ethyl(methyl)amino)-9H-purin-9-yl)propyl)piperidin-3-ol, 140) (2R,3S )-2-(3-(6-morpholino-9H-purin-9-yl )propyl)piperidin-3 -ol, 141) (2R,3S)-2-(3-(6-(piperidin-1-yl)-9H-purin-9-yl)propyl)piperidin-3-ol, 142) (2R,3S)-2-(3-(6-(pyrrolidin-1-yl)-9H-purin-9-yl)propyl)piperidin-3-ol, 143) 1-(3-((2R,3 S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-2-ol, 144) 5,6-dichloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-benzo[d]imidazol-2-ol, 145) (2R,3S)-2-(3-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-ol, 146) (2R,3S)-2-(3-(2-(hydroxymethyl)-4,5-dimethyl-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 147) (2R,3S)-2-(3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 148) (2R,3S)-2-(3-(2-amino-5,6-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol, 149) methyl 7-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-Indole-3-carboxylate, 150) methyl 5-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-indole-3-carboxylate, 151) methyl 6-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-Indole-3-carboxylate, 152) methyl 4-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-indole-3-carboxylate, 153) methyl 6-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-indole-3-carboxylate, 154) methyl 7-chloro-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1H-Indole-3-carboxylate, 155) (2R,3S)-2-(3-(5-chloro-3-cyclopropyl-1H-indazol- 1 -yl)propyl)pipendin-3-ol, 156) (2R,3S)-2-(3-(5-chloro-3-(trifluoromethyl)-1H-indazol-1-yl)propyl)piperidin-3-ol, 157) (2R,3S)-2-(3-(5-chloro-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-1H-indazol-yl)propyl)piperidin-3-ol, 158) (2 R,3S)-2-(3-(6-chloro-3-(1-(difluoromethyl )-1H-pyrazol-4-yl)-1H-indazol-1-yl )propyl)piperidin-3-ol, 159) 1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one, 160) 5-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)- 1H-benzo[d]
    imidazol-2(3H)-one, 161) 6-bromo-1-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)- 1H-benzo[d]imidazol-2(3H)-one, 162) 7-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione, 163) 7-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-3-methyl-1H-purine-2,6(3H,7H)-dione, 164) 9-(3-((2R,3S)-3-hydroxypiperidin-2-yl)propyl)-1-methyl-1H-purine-2,6(3H,9H)-dione, 165) 7-(3-((2R,3S )-3 -hydroxypiperidin-2-yl)propyl)-3 -isobutyl-1-methyl-1H-purine-2,6(3 H,7H)-dione, 166) (2R,3S)-2-((E)-3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 167) (2R,3S)-2-((E)-3-(5-fluoro-4-methyl-1H-benzo[d]imidazol-1-yl)prop-1-enyppipendin-3-ol, 168) (2R,3S)-2-((E)-3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 169) (2R,3S)-2-((E)-3-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 170) (2 R,3S)-2-((E)-3-(5,6-dibromo-1H-benzo[d] imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 171) (2R,3S)-2-((E)-3-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)prop-172) (2 R,3S)-2-((E)-3-(4,5-dimethyl-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 173) (2 R,3S)-2-((E)-3-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 174) (2R,3S)-2-((E)-3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 175) (2 R,3S)-2-((E)-3 -(4-chloro-5-methyl-1H-benzo[d] imidazol-1-yl)prop-1-en-yl)pipendin-3-ol, 176) (2R,3S)-2-((E)-3-(5-bromo-4-nitro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 177) (2 R,3S)-2-((E)-3-(6-bromo-7-nitro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 178) (2R,3S)-2-((E)-3-(4-chloro-5-nitro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 179) (2R,3S)-2-((E)-3-(4,6-difluoro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 180) (2R,3S)-2-((E)-3-(6-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 181) (2R,3S)-2-((E)-3-(7-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 182) (2R,3S)-2-((E)-3-(5,7-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 183) (2R,3S)-2-((E)-3-(5-chloro-7-fluoro-1H-benzo[d]imidazol-1-yl)prop-1-en-1-yl)piperidin-3-ol, 184) (2R,3S)-2-((E)-3-(5-bromo-1H-imidazo[4,5-b]pyridin-1-yl)prop-1-enyl)piperidin-3-ol, 185) (2R,3S)-2-((E)-3-(7-chloro-6-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 186) (2R,3S)-2-((E)-3-(6-bromo-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 187) (2R,3S)-2-((E)-3-(6-bromo-7-chloro-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 188) (2R,3S)-2-((E)-3-(6-chloro-7-methyl-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 189) (2R,3S)-2-((E)-3-(6,7-dichloro-3H-imidazo[4,5-b]pyridin-3-yl)prop-1-enyl)piperidin-3-ol, 190) (2R,3S)-2-((E)-3-(6-(3-chlorophenyl)-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 191) (2R,3S)-2-((E)-3-(6-(3-fluorophenyl)-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 192) (2R,3S )-2-((E)-3-(6-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 193) (2R,3S)-2-((E)-3-(5-bromo-6,7-difluoro-2-methyl-1H-benzo[d]imidazol-1-yl)prop-1-enyl)piperidin-3-ol, 194) (2R,3S)-2-((E)-3-(indolin-1-yl)prop-1-enyl)piperidin-3-ol, 195) (2R,3S)-2-((E)-3-(5-chloroindolin-1-yl)prop-1-enyl)piperidin-3-ol, 196) (2R,3S)-2-((E)-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)prop-1-enyl)piperidin-3-ol, 197) (2R,3S)-2-((E)-3-(6-chloro-1H-indol-1-yl)prop-1-enyl)piperidin-3-ol, 198) (2R,3S)-2-((E)-3-(6-chloro-1H-indazol-1-yl)prop-1-enyl)piperidin-3-ol, 199) (2R,3S)-2-((E)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)prop-1-enyl)piperidin-3-ol, 200) (2R,3S)-2-((E)-3-(5-chloro-1H-pyrazolo[3,4-b]pyridin-1-yl)prop-1-enyl)piperidin-3-ol, 201) (2R,3S)-2-((E)-3-(3,5-dimethyl-1H-indazol-1-yl)prop-1-enyl)piperidin-3-ol, 202) methyl 7-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-carboxylate.
    203) 7-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 204) 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 205) 4-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 206) 6-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 207) 7-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 208) 6-fluoro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 209) 1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylic acid, 210) methyl 4-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylate, 211) methyl 6-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-3-carboxylate, 212) methyl 7-chloro-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-Indole-3-carboxylate, 213) methyl 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-carboxylate, 214) methyl 6-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-1H-indole-carboxylate, 215) 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-N-methyl-1H-indole-3-carboxamide, 216) 5-bromo-1-((E)-3-((2R,3S)-3-hydroxypiperidin-2-yl)allyl)-N,N-dimethyl-1H-indole-3-carboxamide, 217) (2R,3S)-2-((Z)-3-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)-2-fluoroprop-1-enyl)piperidin-3-ol, 218) (2R,3S)-2-((Z)-3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)-2-fluoroprop-1-enyl)piperidin-3-ol, 219) (2R,3S)-2-((Z)-3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)-2-fluoroprop-1-enyl)piperidin-3-ol, 220) (2R,3S)-2-((Z)-3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-2-fluoroprop-1-enyl)piperidin-3-ol, 221) (2R,3S)-2-((E)-3-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)-2-methylprop-1-enyl)piperidin-3-ol, 222) (2R,3S)-2-((E)-3-(5-bromo-4-methyl-1H-benzo[d]imidazol-1-yl)-2-methylprop-1-enyl)piperidin-3-ol, 223) (2R,3S)-2-((E)-3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)-2-methylprop-1-enyl)piperidin-3-ol, 224) (2R,3S)-2-((E)-3-(5,6-dichloro-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)-2-methylprop-1-enyl)piperidin-3-ol, 225) (2R,3S)-2-(3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-ynyl)piperidin-ol, 226) (2R,3S)-2-(3 -(5-bromo-4-methyl-1H-benzo[d]imdazol-1-yl )prop-1-ynyl)piperidin-3-ol, 227) (2R,3S)-2-(3-(5-chloro-4-methyl-1H-benzo[d]imidazol-1-yl)prop-1-ynyl)piperidin-3-ol, 228) (2R,3S)-2-(3-(5,6-dibromo-1H-benzo[d]imidazol-1-yl)prop-1-ynyl)piperidin-ol, 229) (2R,3S)-2-(3-(5-fluoro-4-methyl-1H-benzo[d]imidazo1-1-yl)prop-1-ynyl)piperidin-3-ol, and 230) (2R,3S)-2-((E)-3-(5,6-dichloro-1H-benzo[d]imidazol-1-yl)prop-1-enyl)pyrrolidin-3-ol.
  12. [Claim 12]
    A pharmaceutical composition for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases or fibrosis, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
  13. [Claim 13]
    A method for preparing a compound represented by the following Chemical Formula 1 comprising the steps of.
    reacting a compound represented by the following Chemical Formula 1-A with a compound represented by the following Chemical Formula 1-B in the presence of a base to prepare a compound represented by the following Chemical Formula 1-C; and reacting a compound represented by the Chemical Formula 1-C in the presence of an acid to prepare a compound represented by the following Chemical Formula 1:
    [Chemical Formula 1-A]

    in Chemical Formulas 1, 1-A, 1-B, and 1-C, n, L, X1, X2 and A are as defined in claim 1, X is halogen, and R' and R" are each independently a protecting goup.
  14. [Claim 14]
    A method for preparing a compound represented by the following Chemical Formula 1 -1 comprising the steps of reacting a compound represented by the following Chemical Formula 2-A with a compound represented by the following Chemical Formula 2-B in the presence of a base to prepare a compound represented by the following Chemical Formula 2-C;
    reacting an amine group and a nitro group of the compound represented by the Chemical Formula 2-C to form a ring, thereby preparing a compound represented by the following Chemical Formula 2-D; and reacting a compound represented by the Chemical Formula 2-D in the presence of an acid to prepare a compound represented by the following Chemical Formula 1-1:
    [Chemical Formula 1-1]

    in Chemical Formulas 1-1, 2-A, 2-B, 2-C, and 2-D, n, L, R2 and A are as defined in claim 1, and R' and R" are each independently a protecting group.
  15. [Claim 15]
    A method for preparing a compound represented by the following Chemical Formula 3 comprising the steps of:
    reacting the compound represented by the following Chemical Formula 3-A with (carbethoxymethylene)triphenylphosphorane to prepare a compound represented by the following Chemical Formula 3-B;

    hydrogenating the compound represented by the following Chemical Formula 3-B
    to prepare a compound represented by the following Chemical Formula 3-C;
    hydrolyzing the compound represented by the Chemical Formula 3-C to prepare a compound represented by the following Chemical Formula 3-D;
    subjecting the compound represented by the Chemical Formula 3-D to a carbonyl reduction reaction to prepare a compound represented by the following Chemical Formula 3-E;
    brominating the compound represented by the Chemical Formula 3-E to prepare a compound represented by the following Chemical Formula 3-F;
    subjecting the compound represented by the Chemical Formula 3-F to an azide reaction to prepare a compound represented by the following Chemical Formula 3-G; and aminating the compound represented by the Chemical Formula 3-G to prepare a compound represented by the following Chemical Formula 3.
    in Chemical Formulas 3, 3-A, 3-B, 3-C, 3-D, 3-E, 3-F, and 3-G, n is as defined in claim 1, and R and R" are each independently a protecting group.
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